HIV integrase inhibitors

ABSTRACT

Tricyclic compounds of Formula I are inhibitors of HIV integrase and inhibitors of HIV replication: 
                         
wherein bond a, ring A, R 1 , R 2  and R 3  are defined herein. The compounds are useful for the prophylaxis or treatment of infection by HIV and the prophylaxis, treatment, or delay in the onset of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 11/920,032, filed Nov.11, 2007, now U.S. Pat. No. 7,741,315 which is the National Stage ofInternational Application No. PCT/US2006/017369, filed on May 5, 2006,which claims the benefit of U.S. Provisional Application No. 60/679,431(filed May 10, 2005), the disclosure of which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to tricyclic analogs of hydroxypolyhydro-2,6-naphthyridine dione compounds and pharmaceuticallyacceptable salts thereof, their synthesis, and their use as inhibitorsof the HIV integrase enzyme. The compounds and pharmaceuticallyacceptable salts thereof of the present invention are useful forpreventing or treating infection by HIV and for preventing or treatingor delaying the onset of AIDS.

BACKGROUND OF THE INVENTION

A retrovirus designated human immunodeficiency virus (HIV), particularlythe strains known as HIV type-1 (HIV-1) virus and type-2 (HIV-2) virus,is the etiological agent of the complex disease that includesprogressive destruction of the immune system (acquired immune deficiencysyndrome; AIDS) and degeneration of the central and peripheral nervoussystem. This virus was previously known as LAV, HTLV-III, or ARV. Acommon feature of retrovirus replication is the insertion byvirally-encoded integrase of +proviral DNA into the host cell genome, arequired step in HIV replication in human T-lymphoid and monocytoidcells. Integration is believed to be mediated by integrase in threesteps: assembly of a stable nucleoprotein complex with viral DNAsequences; cleavage of two nucleotides from the 3′ termini of the linearproviral DNA; covalent joining of the recessed 3′ OH termini of theproviral DNA at a staggered cut made at the host target site. The fourthstep in the process, repair synthesis of the resultant gap, may beaccomplished by cellular enzymes.

Nucleotide sequencing of HIV shows the presence of a pol gene in oneopen reading frame [Ratner, L. et al., Nature, 313, 277 (1985)]. Aminoacid sequence homology provides evidence that the pol sequence encodesreverse transcriptase, integrase and an HIV protease [Toh, H. et al.,EMBO J. 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986);Pearl, L. H. et al., Nature, 329, 351 (1987)]. All three enzymes havebeen shown to be essential for the replication of HIV.

It is known that some antiviral compounds which act as inhibitors of HIVreplication are effective agents in the treatment of AIDS and similardiseases, including reverse transcriptase inhibitors such asazidothymidine (AZT) and efavirenz and protease inhibitors such asindinavir and nelfinavir. The compounds of this invention are inhibitorsof HIV integrase and inhibitors of HIV replication. The inhibition ofintegrase in vitro and HIV replication in cells is a direct result ofinhibiting the strand transfer reaction catalyzed by the recombinantintegrase in vitro in HIV infected cells. The particular advantage ofthe present invention is highly specific inhibition of HIV integrase andHIV replication.

The following references are of interest as background:

U.S. Pat. Nos. 6,380,249, 6,306,891, and 6,262,055 disclose2,4-dioxobutyric acids and acid esters useful as HIV integraseinhibitors.

WO 01/00578 discloses 1-(aromatic- orheteroaromatic-substituted)-3-(heteroaromaticsubstituted)-1,3-propanediones useful as HIV integrase inhibitors.

US 2003/0055071 (corresponding to WO 02/30930), WO 02/30426, and WO02/55079 each disclose certain8-hydroxy-1,6-naphthyridine-7-carboxamides as HIV integrase inhibitors.

WO 02/036734 discloses certain aza- and polyaza-naphthalenyl ketones tobe HIV integrase inhibitors.

WO 03/016275 discloses certain compounds having integrase inhibitoryactivity.

WO 03/35076 discloses certain 5,6-dihydroxypyrimidine-4-carboxamides asHIV integrase inhibitors, and WO 03/35077 discloses certainN-substituted 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamides asHIV integrase inhibitors.

WO 03/062204 discloses certain hydroxynaphthyridinone carboxamides thatare useful as HIV integrase inhibitors.

WO 04/004657 discloses certain hydroxypyrrole derivatives that are HIVintegrase inhibitors.

WO 2005/016927 discloses certain nitrogenous condensed ring compoundsthat are HIV integrase inhibitors.

SUMMARY OF THE INVENTION

The present invention is directed to tricyclic analogs of hydroxypolyhydro-2,6-naphthyridine dione compounds. These compounds are usefulin the inhibition of HIV integrase, the prevention of infection by HIV,the treatment of infection by HIV and in the prevention, treatment, anddelay in the onset of AIDS and/or ARC, either as compounds or theirpharmaceutically acceptable salts or hydrates (when appropriate), or aspharmaceutical composition ingredients, whether or not in combinationwith other HIV/AIDS antivirals, anti-infectives, immunomodulators,antibiotics or vaccines. More particularly, the present inventionincludes compounds of Formula I, and pharmaceutically acceptable saltsthereof:

wherein:

-   bond    in the ring is a single bond or a double bond;-   R¹ is C₁₋₆ alkyl, R^(J), or C₁₋₆ alkyl substituted with R^(J),    wherein R^(J) is CycA, AryA, HetA, or HetP;-   R² is H or C₁₋₆ alkyl;-   R³ is:    -   (1) H,    -   (2) halogen,    -   (3) CN,    -   (4) C₁₋₆ alkyl,    -   (5) C₁₋₆ haloalkyl,    -   (6) C₁₋₆ alkyl substituted with OH, O—C₁₋₆ alkyl, O—C₁₋₆        haloalkyl, CN, N(R^(A))R^(B), C(O)N(R^(A))R^(B), C(O)R^(A),        CO₂R^(A), C(O)—N(R^(A))—C₁₋₆ alkylene-OR^(B) with the proviso        that the N(R^(A)) moiety and the OR^(B) moiety are not both        attached to the same carbon of the C₁₋₆ alkylene moiety, SR^(A),        S(O)R^(A), SO₂R^(A), SO₂N(R^(A))R^(B), N(R^(A))C(O)R^(B),        N(R^(A))CO₂R^(B), N(R^(A))SO₂R^(B), N(R^(A))SO₂N(R^(A))R^(B),        N(R^(A))C(O)N(R^(A))R^(B), or OC(O)N(R^(A))R^(B),    -   (7) C(O)R^(A),    -   (8) CO₂R^(A),    -   (9) C(O)N(R^(A))R^(B),    -   (10) C(O)—N(R^(A))—C₁₋₆ alkylene-OR^(B) with the proviso that        the N(R^(A)) moiety and the OR^(B) moiety are not both attached        to the same carbon of the C₁₋₆ alkylene moiety,    -   (11) SR^(A),    -   (12) S(O)R^(A),    -   (13) SO₂R^(A),    -   (14) SO₂N(R^(A))R^(B),    -   (15) N(R^(A))R^(B),    -   (16) N(R^(A))C(O)R^(B),    -   (17) N(R^(A))C(O)OR^(B);    -   (18) N(R^(A))C(O)N(R^(A))R^(B),    -   (19) N(R^(A))C(O)C(O)N(R^(A))R^(B),    -   (20) N(R^(A))SO₂R^(B),    -   (21) N(R^(A))SO₂N(R^(A))R^(B),    -   (22) OC(O)N(R^(A))R^(B), or    -   (23) Y—R^(K), wherein:        -   Y is a single bond, C₁₋₆ alkylene, O, O—C₁₋₆ alkylene, C₁₋₆            alkylene-O, C(O), C(O)—C₁₋₆ alkylene, C₁₋₆ alkylene-C(O),            C(O)—C₁₋₆ alkylene-O, C(O)—C₁₋₆ alkylene-O—C₁₋₆ alkylene,            C(O)N(R^(A)), C(O)N(R^(A))—C₁₋₆ alkylene, C₁₋₆            alkylene-C(O)N(R^(A)), C₁₋₆ alkylene-C(O)N(R^(A))—C₁₋₆            alkylene, S(O), S(O)₂, S(O)—C₁₋₆ alkylene, S(O)₂—C₁₋₆            alkylene, C₁₋₆ alkylene-S(O), or C₁₋₆ alkylene-S(O)₂; and        -   R^(K) is CycB, AryB, HetB, or HetQ;            or, as an alternative, when bond            is a double bond, R² and R³ together with the carbon atoms            to which each is attached form:    -   (i) a benzene ring which is optionally substituted with a total        of from 1 to 4 substituents wherein (a) from zero to 4        substituents are each independently one of substituents (1)        to (25) as defined in part (i) of the definition of AryA and (b)        from zero to 2 substituents are each independently one of the        substituents (1) to (6) as defined in part (ii) of the        definition of AryA, or    -   (ii) a 5- or 6-membered heteroaromatic ring containing from 1 to        4 heteroatoms independently selected from N, O and S, wherein        the heteroaromatic ring is optionally substituted with a total        of from 1 to 3 substituents wherein (a) from zero to 3        substituents are each independently one of substituents (1)        to (26) as defined in part (i) of the definition of HetA and (b)        from zero to 2 substituents are each independently one of the        substituents (1) to (6) as defined in part (ii) of the        definition of HetA;        ring A is a 5- to 9-membered, saturated or mono-unsaturated        heterocyclic ring containing in addition to the nitrogen shared        with the naphthyridine ring from 1 to 3 heteroatoms        independently selected from N, O, and S, wherein each S is        optionally oxidized to S(O) or S(O)₂; and wherein the saturated        or mono-unsaturated heterocyclic ring is optionally substituted        with a total of from 1 to 10 substituents, wherein:    -   (i) from zero to 10 substituents are each independently:        -   (1) halogen,        -   (2) C₁₋₆ alkyl,        -   (3) C₁₋₆ haloalkyl,        -   (4) C₁₋₆ alkyl substituted with OH, O—C₁₋₆ alkyl, O—C₁₋₆            haloalkyl, CN, N(R^(A))R^(B), C(O)N(R^(A))R^(B), C(O)R^(A),            CO₂R^(A), C(O)—N(R^(A))—C₁₋₆ alkylene-OR^(B) with the            proviso that the N(R^(A)) moiety and the OR^(B) moiety are            not both attached to the same carbon of the C₁₋₆ alkylene            moiety, SR^(A), S(O)R^(A), SO₂R^(A), SO₂N(R^(A))R^(B),            N(R^(A))C(O)R^(B), N(R^(A))CO₂R^(B), N(R^(A))SO₂R^(B),            N(R^(A))SO₂N(R^(A))R^(B), N(R^(A))C(O)N(R^(A))R^(B),            OC(O)N(R^(A))R^(B), or OC(O)R^(A),        -   (5) O—C₁₋₆ alkyl,        -   (6) O—C₁₋₆ haloalkyl,        -   (7) oxo,        -   (8) ═C(R^(A))R^(B),        -   (9) C(O)N(R^(A))R^(B),        -   (10) C(O)C(O)N(R^(A))R^(B),        -   (11) C(O)R^(A),        -   (12) CO₂R^(A),        -   (13) SR^(A),        -   (14) S(O)R^(A),        -   (15) SO₂R^(A),        -   (16) SO₂N(R^(A))R^(B), or        -   (17) OH, and    -   (ii) from zero to 3 substituents are each Z—R^(L), wherein:        -   each Z is independently a single bond, C₁₋₆ alkylene, O,            O—C₁₋₆ alkylene, C₁₋₆ alkylene-O, C(O), C(O)—C₁₋₆ alkylene,            C₁₋₆ alkylene-C(O), C(O)—C₁₋₆ alkylene-O, C(O)—C₁₋₆            alkylene-O—C₁₋₆ alkylene, C(O)N(R^(A)), C(O)N(R^(A))—C₁₋₆            alkylene, C₁₋₆ alkylene-C(O)N(R^(A)), C₁₋₆            alkylene-C(O)N(R^(A))—C₁₋₆ alkylene, S(O), S(O)₂, S(O)—C₁₋₆            alkylene, S(O)₂—C₁₋₆ alkylene, C₁₋₆ alkylene-S(O), or C₁₋₆            alkylene-S(O)₂; and        -   each R^(L) is independently CycC, AryC, HetC, or HetR;-   each R^(A) is independently H or C₁₋₆ alkyl;-   each R^(B) is independently H or C₁₋₆ alkyl;-   CycA is a C₃₋₈ cycloalkyl which is optionally substituted with a    total of from 1 to 6 substituents, wherein:    -   (i) from zero to 6 substituents are each independently:        -   (1) halogen,        -   (2) CN        -   (3) C₁₋₆ alkyl,        -   (4) OH,        -   (5) O—C₁₋₆ alkyl,        -   (6) C₁₋₆ haloalkyl, or        -   (7) O—C₁₋₆ haloalkyl, and    -   (ii) from zero to 2 substituents are each independently:        -   (1) CycD,        -   (2) AryD,        -   (3) HetD,        -   (4) HetZ,        -   (5) C₁₋₆ alkyl substituted with CycD, AryD, HetD, or HetZ,            or        -   (6) C(O)-HetZ or C(O)C(O)-HetZ;-   CycB independently has the same definition as CycA;-   each CycC independently has the same definition as CycA;-   AryA is an aryl which is optionally substituted with a total of from    1 to 5 substituents, wherein:    -   (i) from zero to 5 substituents are each independently:        -   (1) C₁₋₆ alkyl,        -   (2) C₁₋₆ alkyl substituted with OH, O—C₁₋₆ alkyl, O—C₁₋₆            haloalkyl, CN, NO₂, N(R^(A))R^(B), C(O)N(R^(A))R^(B),            C(O)R^(A), CO₂R^(A), SR^(A), S(O)R^(A), SO₂R^(A),            SO₂N(R^(A))R^(B), N(R^(A))C(O)R^(B), N(R^(A))CO₂R^(B),            N(R^(A))SO₂R^(B), N(R^(A))SO₂N(R^(A))R^(B),            OC(O)N(R^(A))R^(B), N(R^(A))C(O)N(R^(A))R^(B), or            N(R^(A))C(O)C(O)N(R^(A))R^(B),        -   (3) O—C₁₋₆ alkyl,        -   (4) C₁₋₆ haloalkyl,        -   (5) O—C₁₋₆ haloalkyl,        -   (6) OH,        -   (7) halogen,        -   (8) CN,        -   (9) NO₂,        -   (10) N(R^(A))R^(B),        -   (11) C(O)N(R^(A))R^(B),        -   (12) C(O)R^(A),        -   (13) C(O)—C₁₋₆ haloalkyl,        -   (14) C(O)OR^(A),        -   (15) OC(O)N(R^(A))R^(B),        -   (16) SR^(A),        -   (17) S(O)R^(A),        -   (18) SO₂R^(A),        -   (19) SO₂N(R^(A))R^(B),        -   (20) N(R^(A))SO₂R^(B),        -   (21) N(R^(A))SO₂N(R^(A))R^(B),        -   (22) N(R^(A))C(O)R^(B),        -   (23) N(R^(A))C(O)N(R^(A))R^(B),        -   (24) N(R^(A))C(O)C(O)N(R^(A))R^(B), or        -   (25) N(R^(A))CO₂R^(B), and    -   (ii) from zero to 2 substituents are each independently:        -   (1) CycD,        -   (2) AryD,        -   (3) HetD,        -   (4) HetZ,        -   (5) C₁₋₆ alkyl substituted with CycD, AryD, HetD, or HetZ,            or        -   (6) C(O)-HetZ or C(O)C(O)-HetZ;-   AryB independently has the same definition as AryA;-   each AryC independently has the same definition as AryA;-   HetA is a heteroaryl which is optionally substituted with a total of    from 1 to 5 substituents, wherein:    -   (i) from zero to 5 substituents are each independently:        -   (1) C₁₋₆ alkyl,        -   (2) C₁₋₆ alkyl substituted with OH, O—C₁₋₆ alkyl, O—C₁₋₆            haloalkyl, CN, NO₂, N(R^(A))R^(B), C(O)N(R^(A))R^(B),            C(O)R^(A), CO₂R^(A), SR^(A), S(O)R^(A), SO₂R^(A),            SO₂N(R^(A))R^(B), N(R^(A))C(O)R^(B), N(R^(A))CO₂R^(B),            N(R^(A))SO₂R^(B), N(R^(A))SO₂N(R^(A))R^(B),            OC(O)N(R^(A))R^(B), N(R^(A))C(O)N(R^(A))R^(B), or            N(R^(A))C(O)C(O)N(R^(A))R^(B),        -   (3) O—C₁₋₆ alkyl,        -   (4) C₁₋₆ haloalkyl,        -   (5) O—C₁₋₆ haloalkyl,        -   (6) OH,        -   (7) oxo,        -   (8) halogen,        -   (9) CN,        -   (10) NO₂,        -   (11) N(R^(A))R^(B),        -   (12) C(O)N(R^(A))R^(B),        -   (13) C(O)R^(A),        -   (14) C(O)—C₁₋₆ haloalkyl,        -   (15) C(O)OR^(A),        -   (16) OC(O)N(R^(A))R^(B),        -   (17) SR^(A),        -   (18) S(O)R^(A),        -   (19) SO₂R^(A),        -   (20) SO₂N(R^(A))R^(B),        -   (21) N(R^(A))SO₂R^(B),        -   (22) N(R^(A))SO₂N(R^(A))R^(B),        -   (23) N(R^(A))C(O)R^(B),        -   (24) N(R^(A))C(O)N(R^(A))R^(B),        -   (25) N(R^(A))C(O)C(O)N(R^(A))R^(B), or        -   (26) N(R^(A))CO₂R^(B), and    -   (ii) from zero to 2 substituents are each independently:        -   (1) CycD,        -   (2) AryD,        -   (3) HetD,        -   (4) HetZ,        -   (5) C₁₋₆ alkyl substituted with CycD, AryD, HetD, or HetZ,            or        -   (6) C(O)-HetZ or C(O)C(O)-HetZ;-   HetB independently has the same definition as HetA;-   each HetC independently has the same definition as HetA;-   HetP is (i) a 4- to 7-membered, saturated or mono-unsaturated    heterocyclic ring containing at least one carbon atom and from 1 to    4 heteroatoms independently selected from N, O and S, where each S    is optionally oxidized to S(O) or S(O)₂ or (ii) a 6- to 10-membered    saturated or mono-unsaturated, bridged or fused heterobicyclic ring    containing from 1 to 4 heteroatoms independently selected from N, O    and S, where each S is optionally oxidized to S(O) or S(O)₂; and    wherein the saturated or mono-unsaturated heterocyclic or    heterobicyclic ring is optionally substituted with a total of from 1    to 4 substituents, wherein:    -   (i) from zero to 4 substituents are each independently halogen,        C₁₋₆ alkyl, C₁₋₆ haloalkyl, O—C₁₋₆ alkyl, O—C₁₋₆ haloalkyl, oxo,        C(O)N(R^(A))R^(B), C(O)C(O)N(R^(A))R^(B), C(O)R^(A), CO₂R^(A),        SR^(A), S(O)R^(A), SO₂R^(A), or SO₂N(R^(A))R^(B), and    -   (ii) from zero to 2 substituents are each independently CycD,        AryD, HetD, or C₁₋₆ alkyl substituted with CycD, AryD, HetD;-   HetQ independently has the same definition as HetP;-   each HetR independently has the same definition as HetP;-   each CycD is independently a C₃₋₈ cycloalkyl which is optionally    substituted with from 1 to 4 substituents each of which is    independently halogen, C₁₋₆ alkyl, OH, O—C₁₋₆ alkyl, or C₁₋₆    haloalkyl;-   each AryD is independently phenyl or naphthyl, wherein the phenyl or    naphthyl is optionally substituted with from 1 to 5 substituents    each of which is independently any one of the substituents (1)    to (25) as set forth above in part (i) of the definition of AryA;-   each HetD is independently a 5- or 6-membered heteroaromatic ring    containing from 1 to 4 heteroatoms independently selected from N, O    and S, wherein the heteroaromatic ring is optionally substituted    with from 1 to 4 substituents each of which is independently any one    of the substituents (1) to (26) as set forth above in part (i) of    the definition of HetA;-   each HetZ is independently a 4- to 7-membered, saturated or    mono-unsaturated heterocyclic ring containing at least one carbon    atom and from 1 to 4 heteroatoms independently selected from N, O    and S, where each S is optionally oxidized to S(O) or S(O)₂, wherein    the saturated or mono-unsaturated heterocyclic ring is optionally    substituted with from 1 to 4 substituents each of which is    independently halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, O—C₁₋₆ alkyl,    O—C₁₋₆ haloalkyl, oxo, C(O)N(R^(A))R^(B), C(O)C(O)N(R^(A))R^(B),    C(O)R^(A), CO₂R^(A), SR^(A), S(O)R^(A), SO₂R^(A), or    SO₂N(R^(A))R^(B);-   each aryl is independently (i) phenyl, (ii) a 9- or 10-membered    bicyclic, fused carbocyclic ring system in which at least one ring    is aromatic, or (iii) an 11- to 14-membered tricyclic, fused    carbocyclic ring system in which at least one ring is aromatic; and-   each heteroaryl is independently (i) a 5- or 6-membered    heteroaromatic ring containing from 1 to 4 heteroatoms independently    selected from N, O and S, wherein each N is optionally in the form    of an oxide, or (ii) a 9- or 10-membered bicyclic, fused ring system    containing from 1 to 4 heteroatoms independently selected from N, O    and S, wherein either one or both of the rings contain one or more    of the heteroatoms, at least one ring is aromatic, each N is    optionally in the form of an oxide, and each S in a ring which is    not aromatic is optionally S(O) or S(O)₂.

The present invention also includes pharmaceutical compositionscontaining a compound of Formula I or a pharmaceutically acceptable saltthereof. The present invention further includes methods for thetreatment of AIDS, the delay in the onset of AIDS, the prophylaxis ofAIDS, the prophylaxis of infection by HIV, and the treatment ofinfection by HIV.

Other embodiments, aspects and features of the present invention areeither further described in or will be apparent from the ensuingdescription, examples and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes compounds of Formula I above, andpharmaceutically acceptable salts thereof. These compounds and theirpharmaceutically acceptable salts are HIV integrase inhibitors (e.g.,HIV-1 integrase inhibitors).

A first embodiment of the present invention (alternatively referred toherein as “Embodiment E1”) is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein ring A is a 5- to9-membered, saturated or mono-unsaturated heterocyclic ring containingin addition to the nitrogen shared with the naphthyridine ring from 1 to3 heteroatoms independently selected from N, O, and S, wherein each S isoptionally oxidized to S(O) or S(O)₂; and wherein the saturated ormono-unsaturated heterocyclic ring is optionally substituted with atotal of from 1 to 6 substituents, wherein:

-   -   (i) from zero to 6 substituents are each independently:        -   (1) halogen,        -   (2) C₁₋₆ alkyl,        -   (3) C₁₋₆ haloalkyl,        -   (4) C₁₋₆ alkyl substituted with OH, O—C₁₋₆ alkyl, O—C₁₋₆            haloalkyl, CN, N(R^(A))R^(B), C(O)N(R^(A))R^(B), C(O)R^(A),            CO₂R^(A), C(O)—N(R^(A))—C₁₋₆ alkylene-OR^(B) with the            proviso that the N(R^(A)) moiety and the OR^(B) moiety are            not both attached to the same carbon of the C₁₋₆ alkylene            moiety, SR^(A), S(O)R^(A), SO₂R^(A), SO₂N(R^(A))R^(B),            N(R^(A))C(O)R^(B), N(R^(A))CO₂R^(B), N(R^(A))SO₂R^(B),            N(R^(A))SO₂N(R^(A))R^(B), N(R^(A))C(O)N(R^(A))R^(B), or            OC(O)N(R^(A))R^(B),        -   (5) O—C₁₋₆ alkyl,        -   (6) O—C₁₋₆ haloalkyl,        -   (7) oxo,        -   (8) ═C(R^(A))R^(B),        -   (9) C(O)N(R^(A))R^(B),        -   (10) C(O)C(O)N(R^(A))R^(B),        -   (11) C(O)R^(A),        -   (12) CO₂R^(A),        -   (13) SR^(A),        -   (14) S(O)R^(A),        -   (15) SO₂R^(A), or        -   (16) SO₂N(R^(A))R^(B), and    -   (ii) from zero to 2 substituents are each Z—R^(L), wherein:        -   each Z is independently a single bond, C₁₋₆ alkylene, O,            O—C₁₋₆ alkylene, C₁₋₆ alkylene-O, C(O), C(O)—C₁₋₆ alkylene,            C₁₋₆ alkylene-C(O), C(O)—C₁₋₆ alkylene-O, C(O)—C₁₋₆            alkylene-O—C₁₋₆ alkylene, C(O)N(R^(A)), C(O)N(R^(A))—C₁₋₆            alkylene, C₁₋₆ alkylene-C(O)N(R^(A)), C₁₋₆            alkylene-C(O)N(R^(A))—C₁₋₆ alkylene, S(O), S(O)₂, S(O)—C₁₋₆            alkylene, S(O)₂—C₁₋₆ alkylene, C₁₋₆ alkylene-S(O), or C₁₋₆            alkylene-S(O)₂; and        -   each R^(L) is independently CycC, AryC, HetC, or HetR;            and all other variables are as originally defined (i.e., as            defined in the Summary of the Invention).

A second embodiment of the present invention (Embodiment E2) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein R¹ is R^(J) or C₁₋₆ alkyl substituted with R^(J); and all othervariables are as originally defined or as defined in Embodiment E1.

A third embodiment of the present invention (Embodiment E3) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein R¹ is C₁₋₆ alkyl substituted with R^(J); and all other variablesare as originally defined or as defined in Embodiment E1.

A fourth embodiment of the present invention (Embodiment E4) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein R¹ is C₁₋₄ alkyl substituted with R^(J); and all other variablesare as originally defined or as defined in Embodiment E1.

A fifth embodiment of the present invention (Embodiment E5) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein R¹ is (CH₂)₁₋₂R^(J) or CH(CH₃)—R^(J); and all other variablesare as originally defined or as defined in Embodiment E1.

A sixth embodiment of the present invention (Embodiment E6) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein R¹ is CH₂—R^(J); and all other variables are as originallydefined or as defined in Embodiment E1.

A seventh embodiment of the present invention (Embodiment E7) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein R^(J) is AryA or HetA; and all other variables are as originallydefined or as defined in any one of the preceding embodiments.

An eighth embodiment of the present invention (Embodiment E8) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein R^(J) is phenyl, naphthyl, 2,3-dihydrobenzo-1,4-dioxinyl,benzo-1,3-dioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, orquinazolinyl, any of which is optionally substituted with a total offrom 1 to 4 substituents, wherein:

-   -   (a) from zero to 4 substituents are each independently:        -   (1) C₁₋₆ alkyl,        -   (2) O—C₁₋₆ alkyl,        -   (3) C₁₋₆ haloalkyl,        -   (4) O—C₁₋₆ haloalkyl,        -   (5) OH,        -   (6) halogen,        -   (7) CN,        -   (8) N(R^(A))R^(B),        -   (9) C(O)N(R^(A))R^(B),        -   (10) S(O)R^(A),        -   (11) SO₂R^(A),        -   (12) N(R^(A))SO₂R^(B),        -   (13) N(R^(A))SO₂N(R^(A))R^(B),        -   (14) N(R^(A))C(O)R^(B), or        -   (15) N(R^(A))C(O)C(O)N(R^(A))R^(B), and    -   (b) from zero to 2 substituents are each independently HetZ or        C(O)-HetZ,        -   wherein HetZ is a 5- or 6-membered saturated heterocyclic            ring containing a total of from 1 to 2 heteroatoms selected            from 1 to 2 N atoms, zero to 1 O atom, and zero to 1 S atom,            wherein the S atom is optionally S(O) or SO₂, wherein the            saturated heterocyclic ring is optionally substituted with            from 1 to 2 substituents each of which is C₁₋₄ alkyl, oxo,            C(O)N(R^(A))R^(B), C(O)R^(A), CO₂R^(A), or SO₂R^(A),        -   and with the proviso that when HetZ is attached to the rest            of the compound via the C(O) moiety, then HetZ is attached            to the C(O) via a ring N atom;            and all other variables are as originally defined or as            defined in any one of the preceding embodiments.

A ninth embodiment of the present invention (Embodiment E9) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein R¹ is CH₂—R^(J); is as defined in Embodiment E8; and all othervariables are as originally defined or as defined in Embodiment E1.

A tenth embodiment of the present invention (Embodiment E10) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein R¹ is:

the asterisk * denotes the point of attachment of R¹ to the rest of thecompound; V¹ and V² are each independently:

-   -   (1) H,    -   (2) C₁₋₄ alkyl,    -   (3) OH,    -   (4) O—C₁₋₄ alkyl,    -   (5) C₁₋₄ haloalkyl,    -   (6) O—C₁₋₄ haloalkyl,    -   (7) halogen,    -   (8) CN,    -   (9) N(R^(A))R^(B),    -   (10) C(O)N(R^(A))R^(B),    -   (11) C(O)R^(A),    -   (12) C(O)OR^(A),    -   (13) SR^(A),    -   (14) S(O)R^(A),    -   (15) SO₂R^(A),    -   (16) N(R^(A))SO₂R^(B),    -   (17) N(R^(A))SO₂N(R^(A))R^(B),    -   (18) N(R^(A))C(O)R^(B),    -   (19) N(R^(A))C(O)C(O)N(R^(A))R^(B),    -   (20) HetD,    -   (21) HetZ, or    -   (22) C(O)-HetZ,        -   wherein            -   HetD is a 5- or 6-membered heteroaromatic ring                containing a total of from 1 to 3 heteroatoms                independently selected from 1 to 3 N atoms, from zero to                1 O atom, and from zero to 1 S atom, wherein the                heteroaromatic ring is optionally substituted with 1 or                2 substituents each of which is independently C₁₋₄                alkyl, OH, O—C₁₋₄ alkyl, halogen, CN, C(O)N(R^(A))R^(B),                C(O)R^(A), C(O)OR^(A), or SO₂R^(A),            -   HetZ is a 5- or 6-membered saturated heterocyclic ring                containing a total of from 1 to 2 heteroatoms selected                from 1 to 2 N atoms, zero to 1 O atom, and zero to 1 S                atom, wherein the S atom is optionally S(O) or SO₂,                wherein the saturated heterocyclic ring is optionally                substituted with from 1 to 2 substituents each of which                is independently C₁₋₄ alkyl, oxo, C(O)N(R^(A))R^(B),                C(O)R^(A), CO₂R^(A), or SO₂R^(A),            -   and with the proviso that when HetZ is attached to the                rest of the compound via the C(O) moiety, then HetZ is                attached to the C(O) via a ring N atom;                or alternatively V¹ and V² are respectively located on                adjacent carbons in the phenyl ring and together form                methylenedioxy or ethylenedioxy; and

-   V³ is:    -   (1) H,    -   (2) C₁₋₄ alkyl,    -   (3) O—C₁₋₄ alkyl,    -   (4) C₁₋₄ haloalkyl,    -   (5) O—C₁₋₄ haloalkyl, or    -   (6) halogen;        and all other variables are as originally defined or as defined        in Embodiment E1.

An eleventh embodiment of the present invention (Embodiment E11) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein R¹ is CH₂—R^(J); and R^(J) is 4-fluorophenyl or3-chloro-4-fluorophenyl; and all other variables are as originallydefined or as defined in Embodiment E1.

A twelfth eleventh embodiment of the present invention (Embodiment E12)is a compound of Formula I, or a pharmaceutically acceptable saltthereof, wherein R² is H or C₁₋₆ alkyl; and R³ is H, C₁₋₆ alkyl,C(O)N(R^(A))R^(B), SO₂N(R^(A))R^(B), or C₁₋₆ alkyl substituted withC(O)N(R^(A))R^(B) or SO₂N(R^(A))R^(B); and all other variables are asoriginally defined or as defined in any one of the precedingembodiments.

A thirteenth embodiment of the present invention (Embodiment E13) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein R² and R³ are each independently H or C₁₋₄ alkyl; and all othervariables are as originally defined or as defined in any one of thepreceding embodiments.

A fourteenth embodiment of the present invention (Embodiment E14) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein R² and R³ are both H; and all other variables are as originallydefined or as defined in any one of the preceding embodiments.

A fifteenth embodiment of the present invention (Embodiment E15) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein ring A is:

wherein each R* is independently: (1) H, (2), C₁₋₆ alkyl, (3) C(O)R^(A),(4) SO₂R^(A), (5) CO₂R^(A), or (6) C₁₋₆ alkyl substituted with OH,O—C₁₋₆ alkyl, N(R^(A))R^(B), C(O)N(R^(A))R^(B), C(O)R^(A), CO₂R^(A),C(O)—N(R^(A))—C₁₋₆ alkylene-OR^(B) with the proviso that the N(R^(A))moiety and the OR^(B) moiety are not both attached to the same carbon ofthe C₁₋₆ alkylene moiety, S(O)R^(A), SO₂R^(A), SO₂N(R^(A))R^(B),N(R^(A))C(O)R^(B), N(R^(A))SO₂R^(B), or OC(O)R^(A); Q is O orC(R^(A))R^(B); and the

's denote the points at which ring A is attached to the remainder of thenaphthyridine ring with which it is fused; and all other variables areas originally defined or as defined in any one of the precedingembodiments.

A sub-embodiment of Embodiment E15 is a compound of Formula I, or apharmaceutically acceptable salt thereof, wherein each R* isindependently: (1) H, (2), C₁₋₆ alkyl, (3) C(O)R^(A), (4) SO₂R^(A), or(5) CO₂R^(A); and ring A, Q and all other variables are as defined inEmbodiment E15.

A sixteenth embodiment of the present invention (Embodiment E16) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein each R^(A) and R^(B) is independently H or C₁₋₄ alkyl; and allother variables are as originally defined or as defined in any one ofthe preceding embodiments.

A seventeenth embodiment of the present invention (Embodiment E17) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein each R^(A) and R^(B) is independently H or C₁₋₃ alkyl; and allother variables are as originally defined or as defined in any one ofthe preceding embodiments.

An eighteenth embodiment of the present invention (Embodiment E18) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein each R^(A) and R^(B) is independently H or methyl; and all othervariables are as originally defined or as defined in any one of thepreceding embodiments.

A nineteenth embodiment of the present invention (Embodiment E19) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein bond

in the ring is a single bond; and all other variables are as originallydefined or as defined in any one of the preceding embodiments.

A twentieth embodiment of the present invention (Embodiment E20) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein CycA, CycB, and CycC are each independently a C₃₋₇ cycloalkylwhich is optionally substituted with from 1 to 2 substituents each ofwhich is independently C₁₋₄ alkyl, O—C₁₋₄ alkyl, phenyl, or benzyl; andall other variables are as originally defined or as defined in any oneof the preceding embodiments. In an aspect of this embodiment, CycA,CycB, and CycC are each independently cyclopropane, cyclobutane,cyclopentane, or cyclohexane, any of which is optionally substitutedwith methyl or phenyl; and all other variables are as originally definedor as defined in any one of the preceding embodiments.

A twenty-first embodiment of the present invention (Embodiment E21) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein each aryl (i.e., the aryl incorporated into the definitions ofAryA, AryB, and AryC) is independently selected from the groupconsisting of phenyl, naphthyl, tetrahydronaphthyl (tetralinyl),indenyl, anthracenyl, or fluorenyl; and all other variables are asoriginally defined or as defined in any one of the precedingembodiments. In an aspect of this embodiment, each aryl is independentlyselected from the group consisting of phenyl and naphthyl. In anotheraspect of this embodiment, each aryl is phenyl.

A twenty-second embodiment of the present invention (Embodiment E22) isa compound of Formula I, or a pharmaceutically acceptable salt thereof,wherein each heteroaryl (i.e., the heteroaryl incorporated into thedefinitions of HetA, HetB, and HetC) is independently selected from thegroup consisting of pyrrolyl, pyrazolyl, thienyl, furanyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, oxatriazolyl,thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl (or pyridyl),pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzofuranyl, indolyl,indazolyl, naphthyridinyl, isobenzofuranyl, benzopiperidinyl,benzisoxazolyl, benzoxazolyl, chromenyl, quinolinyl, isoquinolinyl,cinnolinyl, quinazolinyl, 2,3-dihydrobenzo-1,4-dioxinyl

and benzo-1,3-dioxolyl

and all other variables are as originally defined or as defined in anyone of the preceding embodiments. In an aspect of this embodiment, eachheteroaryl is independently a 5- or 6-membered heteroaromatic ringselected from the group consisting of pyrrolyl, pyrazolyl, thienyl,furanyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl,oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl (orpyridyl), pyrazinyl, pyrimidinyl, and pyridazinyl.

A twenty-third embodiment of the present invention (Embodiment E23) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein HetP and HetQ are each independently a 4- to 7-membered,saturated heterocyclic ring containing from 1 to 3 heteroatomsindependently selected from N, O and S, where each S is optionallyoxidized to S(O) or SO₂; wherein the heterocyclic ring is optionallysubstituted with from 1 to 4 substituents each of which is independentlyhalogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, O—C₁₋₄ alkyl, O—C₁₋₄ haloalkyl,oxo, C(O)N(R^(A))R^(B), C(O)C(O)N(R^(A))R^(B), C(O)R^(A), CO₂R^(A),SR^(A), S(O)R^(A), SO₂R^(A), or SO₂N(R^(A))R^(B); and all othervariables are as originally defined or as defined in any one of thepreceding embodiments. In an aspect of this embodiment, HetP and HetQare each independently selected from the group consisting of azetidinyl,piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl,imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl,pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, azepanyl,diazepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, and dioxanyl.

A twenty-fourth embodiment of the present invention (Embodiment E24) isa compound of Formula I, or a pharmaceutically acceptable salt thereof,wherein each CycD is independently a C₃₋₇ cycloalkyl which is optionallysubstituted with from 1 to 2 substituents each of which is independentlyC₁₋₄ alkyl, O—C₁₋₄ alkyl, phenyl, or benzyl. In an aspect of thisembodiment, each CycD is independently cyclopropane, cyclobutane,cyclopentane, or cyclohexane, any of which is optionally substitutedwith methyl or phenyl; and all other variables are as originally definedor as defined in any one of the preceding embodiments.

A twenty-fifth embodiment of the present invention (Embodiment E25) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein each AryD is independently phenyl which is optionallysubstituted with from 1 to 3 substituents each of which is independently(1) C₁₋₄ alkyl, (2) OH, (3) O—C₁₋₄ alkyl, (4) C₁₋₄ haloalkyl, (5) O—C₁₋₄haloalkyl, (6) halogen, (7) CN, (8) N(R^(A))R^(B), (9)C(O)N(R^(A))R^(B), (10) C(O)R^(A), (11) C(O)OR^(A), (12) SR^(A), (13)S(O)R^(A), (14) SO₂R^(A), (15) N(R^(A))SO₂R^(B), (16)N(R^(A))SO₂N(R^(A))R^(B), (17) N(R^(A))C(O)R^(B), or (18)N(R^(A))C(O)C(O)N(R^(A))R^(B); and all other variables are as originallydefined or as defined in any one of the preceding embodiments.

A twenty-sixth embodiment of the present invention (Embodiment E26) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein each AryD is independently phenyl which is optionallysubstituted with from 1 to 3 substituents each of which is independently(1) C₁₋₄ alkyl, (2) C₁₋₄ haloalkyl, (3) OH, (4) O—C₁₋₄ alkyl, (5)halogen, (6) CN, (7) C(O)NH₂, (8) C(O)NH(C₁₋₄ alkyl), (9) C(O)N(C₁₋₄alkyl)₂, or (10) SO₂—C₁₋₄ alkyl; and all other variables are asoriginally defined or as defined in any one of the precedingembodiments. In an aspect of this embodiment, the 1 to 3 substituentsare each independently selected from the group consisting of CH₃, CF₃,OH, OCH₃, Cl, Br, F, CN, C(O)NH₂, C(O)NH(CH₃), C(O)N(CH₃)₂, or SO₂CH₃.

A twenty-seventh embodiment of the present invention (Embodiment E27) isa compound of Formula I, or a pharmaceutically acceptable salt thereof,wherein each HetD is independently a 5- or 6-membered heteroaromaticring independently selected from the group consisting of pyrrolyl,pyrazolyl, thienyl, furanyl, imidazolyl, triazolyl, tetrazolyl,oxazolyl, isooxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl,isothiazolyl, thiadiazolyl, pyridinyl (or pyridyl), pyrazinyl,pyrimidinyl, pyridazinyl, and triazinyl; wherein the heteroaromatic ringis optionally substituted with from 1 to 3 substituents each of which isindependently (1) C₁₋₄ alkyl, (2) OH, (3) O—C₁₋₄ alkyl, (4) C₁₋₄haloalkyl, (5) O—C₁₋₄ haloalkyl, (6) halogen, (7) CN, (8) N(R^(A))R^(B),(9) C(O)N(R^(A))R^(B), (10) C(O)R^(A), (11) C(O)OR^(A), (12) SR^(A),(13) S(O)R^(A), (14) SO₂R^(A), (15) N(R^(A))SO₂R^(B), (16)N(R^(A))SO₂N(R^(A))R^(B), (17) N(R^(A))C(O)R^(B), or (18)N(R^(A))C(O)C(O)N(R^(A))R^(B); and all other variables are as originallydefined or as defined in any one of the preceding embodiments.

A twenty-eighth embodiment of the present invention (Embodiment E28) isa compound of Formula I, or a pharmaceutically acceptable salt thereof,wherein each HetD is independently a 5- or 6-membered heteroaromaticring independently selected from the group consisting of theheteroaromatic rings set forth in Embodiment E27, wherein theheteroaromatic ring is optionally substituted with from 1 to 3substituents each of which is independently (1) C₁₋₄ alkyl, (2) C₁₋₄haloalkyl, (3) OH, (4) O—C₁₋₄ alkyl, (5) halogen, (6) CN, (7) C(O)NH₂,(8) C(O)NH(C₁₋₄ alkyl), (9) C(O)N(C₁₋₄ alkyl)₂, or (10) SO₂—C₁₋₄ alkyl;and all other variables are as originally defined or as defined in anyone of the preceding embodiments. In an aspect of this embodiment, the 1to 3 substituents are each independently selected from the groupconsisting of CH₃, CF₃, OH, OCH₃, Cl, Br, F, CN, C(O)NH₂, C(O)NH(CH₃),C(O)N(CH₃)₂, or SO₂CH₃.

A twenty-ninth embodiment of the present invention (Embodiment E29) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein each HetD is independently a 5- or 6-membered heteroaromaticring containing a total of from 1 to 3 heteroatoms independentlyselected from 1 to 3 N atoms, from zero to 1 O atom, and from zero to 1S atom, wherein the heteroaromatic ring is optionally substituted with 1or 2 substituents each of which is independently C₁₋₄ alkyl, OH, O—C₁₋₄alkyl, halogen, CN, C(O)N(R^(A))R^(B), C(O)R^(A), C(O)OR^(A), orSO₂R^(A); and all other variables are as originally defined or asdefined in any one of the preceding embodiments.

A thirtieth embodiment of the present invention (Embodiment E30) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein each HetZ is independently a 4- to 7-membered, saturatedheterocyclic ring containing from 1 to 3 heteroatoms independentlyselected from N, O and S, where each S is optionally oxidized to S(O) orSO₂; wherein the heterocyclic ring is optionally substituted with from 1to 4 substituents each of which is independently halogen, C₁₋₄ alkyl,C₁₋₄ haloalkyl, O—C₁₋₄ alkyl, O—C₁₋₄ haloalkyl, oxo, C(O)N(R^(A))R^(B),C(O)C(O)N(R^(A))R^(B), C(O)R^(A), CO₂R^(A), SR^(A), S(O)R^(A), SO₂R^(A),or SO₂N(R^(A))R^(B); and all other variables are as originally definedor as defined in any one of the preceding embodiments. In an aspect ofthis embodiment, each HetZ is independently a saturated heterocyclicring selected from the group consisting of azetidinyl, piperidinyl,morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl,oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl,tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl,hexahydropyrimidinyl, thiazinanyl, thiazepanyl, azepanyl, diazepanyl,tetrahydropyranyl, tetrahydrothiopyranyl, and dioxanyl, wherein the ringis optionally substituted with from 1 to 2 substituents each of which isindependently C₁₋₄ alkyl or oxo.

A thirty-first embodiment of the present invention (Embodiment E31) is acompound of Formula I, or a pharmaceutically acceptable salt thereof,wherein Y is a single bond, (CH₂)₁₋₂, O, O—(CH₂)₁₋₂, (CH₂)₁₋₂—O, C(O),C(O)—(CH₂)₁₋₂, (CH₂)₁₋₂—C(O), C(O)—(CH₂)₁₋₂—O, C(O)—(CH₂)₁₋₂—O—(CH₂)₁₋₂,C(O)N(R^(A)), C(O)N(R^(A))—(CH₂)₁₋₂, (CH₂)₁₋₂—C(O)N(R^(A)),(CH₂)₁₋₂—C(O)N(R^(A))—(CH₂)₁₋₂, S(O), S(O)₂, S(O)—(CH₂)₁₋₂,S(O)₂—(CH₂)₁₋₂, (CH₂)₁₋₂—S(O), or (CH₂)₁₋₂—S(O)₂; and all othervariables are as originally defined or as defined in any one of thepreceding embodiments.

A thirty-second embodiment of the present invention (Embodiment E32) isa compound of Formula I, or a pharmaceutically acceptable salt thereof,wherein each Z is independently a single bond, (CH₂)₁₋₂, O, O—(CH₂)₁₋₂,(CH₂)₁₋₂—O, C(O), C(O)—(CH₂)₁₋₂, (CH₂)₁₋₂—C(O), C(O)—(CH₂)₁₋₂—O,C(O)—(CH₂)₁₋₂—O—(CH₂)₁₋₂, C(O)N(R^(A)), C(O)N(R^(A))—(CH₂)₁₋₂,(CH₂)₁₋₂—C(O)N(R^(A)), (CH₂)₁₋₂—C(O)N(R^(A))—(CH₂)₁₋₂, S(O), S(O)₂,S(O)—(CH₂)₁₋₂, S(O)₂—(CH₂)₁₋₂, (CH₂)₁₋₂—S(O), or (CH₂)₁₋₂—S(O)₂; and allother variables are as originally defined or as defined in any one ofthe preceding embodiments.

A first class of the present invention (alternatively referred to hereinas “Class C1”) includes compounds of Formula IIa and IIb andpharmaceutically acceptable salts thereof:

wherein:

-   bond    in the ring is a single bond or a double bond;-   R¹, R² and R³ are each as originally defined above or as defined in    any one of the preceding embodiments;-   n is an integer equal to zero, 1, 2, or 3;-   W is O or N—R⁸;-   R⁴ is:    -   (1) H,    -   (2) C₁₋₆ alkyl, or    -   (3) C₁₋₆ alkyl substituted with OH or OC(O)R^(A);-   each R⁵ is independently:    -   (1) H,    -   (2) C₁₋₆ alkyl,    -   (3) C₁₋₆ alkyl substituted with OH,    -   (4) OH, or    -   (5) —R^(L);-   each R⁹ is independently H or C₁₋₆ alkyl;-   alternatively, R⁵ and R⁹ attached to the same ring carbon atom    together form oxo or ═C(R^(A))R^(B);-   R⁶ and R⁷ are each independently H, C₁₋₆ alkyl, or C₁₋₆ alkyl    substituted with OH; and-   R⁸ is:    -   (1) H,    -   (2) C₁₋₆ alkyl,    -   (3) C₁₋₆ haloalkyl,    -   (4) C₁₋₆ alkyl substituted with OH, O—C₁₋₆ alkyl, N(R^(A))R^(B),        C(O)N(R^(A))R^(B), C(O)R^(A), CO₂R^(A), C(O)—N(R^(A))—C₁₋₆        alkylene-OR^(B) with the proviso that the N(R^(A)) moiety and        the OR^(B) moiety are not both attached to the same carbon of        the C₁₋₆ alkylene moiety, S(O)R^(A), SO₂R^(A), SO₂N(R^(A))R^(B),        N(R^(A))C(O)R^(B), N(R^(A))SO₂R^(B), or OC(O)R^(A), or    -   (5) Z—R^(L);        -   wherein R^(A), R^(B), Z and R^(L) are each as originally            defined above.

It is understood that n=0 means a 5-membered ring with a direct bondbetween the ring N atom shared with the naphthyridine ring and the ringcarbon to which R⁴ is attached

A subclass of the first class (alternatively referred to as “SubclassSC1-1”) includes compounds of Formula IIa and IIb, and pharmaceuticallyacceptable salts thereof, wherein R¹ is as defined in Embodiment E10;and all other variables are as originally defined Class C1.

A second class of the present invention (Class C2) includes compounds ofFormula IIa′ and IIb′ and pharmaceutically acceptable salts thereof:

wherein:

-   R⁴ is H or C₁₋₆ alkyl;-   each R⁵ is independently H or C₁₋₆ alkyl;-   R⁶ and R⁷ are each independently H or C₁₋₆ alkyl; and-   R⁸ is:    -   (1) H,    -   (2) C₁₋₆ alkyl,    -   (3) C₁₋₆ haloalkyl,    -   (4) C₁₋₆ alkyl substituted with C(O)N(R^(A))R^(B), C(O)R^(A),        CO₂R^(A), C(O)—N(R^(A))—C₁₋₆ alkylene-OR^(B) with the proviso        that the N(R^(A)) moiety and the OR^(B) moiety are not both        attached to the same carbon of the C₁₋₆ alkylene moiety,        S(O)R^(A), SO₂R^(A), or SO₂N(R^(A))R^(B), or    -   (5) Z—R^(L);        and all other variables are as originally defined in Class C1.

A subclass of the second class (Subclass SC2-1) includes compounds ofFormula IIa′ and IIb′, and pharmaceutically acceptable salts thereof,wherein W is O, NH, or N—C₁₋₆ alkyl; and all other variables are asoriginally defined in the second class.

Another subclass of the second class (Subclass SC2-2) includes compoundsof Formula IIa′ and IIb′, and pharmaceutically acceptable salts thereof,wherein W is O, NH, or N—C₁₋₄ alkyl; and all other variables are asoriginally defined in the second class.

Another subclass of the second class (Subclass SC2-3) includes compoundsof Formula IIa′ and IIb′, and pharmaceutically acceptable salts thereof,wherein W is O; and all other variables are as originally defined in thesecond class.

Still another subclass of the second class (Subclass SC2-4) includescompounds of Formula IIa′ and IIb′, and pharmaceutically acceptablesalts thereof, wherein W is NH or N—C₁₋₄ alkyl; and all other variablesare as originally defined in the second class.

Still another subclass of the second class (Subclass SC2-5) includescompounds of Formula IIa′ and IIb′, and pharmaceutically acceptablesalts thereof, wherein W is NH or N—C₁₋₃ alkyl; and all other variablesare as originally defined in the second class.

Still another subclass of the second class (Subclass SC2-6) includescompounds of Formula IIa′ and IIb′, and pharmaceutically acceptablesalts thereof, wherein W is NH or N—CH₃; and all other variables are asoriginally defined in the second class.

Still another subclass of the second class (Subclass SC2-7) includescompounds of Formula IIa′ and IIb′, and pharmaceutically acceptablesalts thereof, wherein Z is a single bond, (CH₂)₁₋₂, O, O—(CH₂)₁₋₂,(CH₂)₁₋₂—O, C(O), C(O)—(CH₂)₁₋₂, (CH₂)₁₋₂—C(O), C(O)—(CH₂)₁₋₂—O,C(O)—(CH₂)₁₋₂—O—(CH₂)₁₋₂, C(O)N(R^(A)), C(O)N(R^(A))—(CH₂)₁₋₂,(CH₂)₁₋₂—C(O)N(R^(A)), (CH₂)₁₋₂—C(O)N(R^(A))—(CH₂)₁₋₂, S(O), S(O)₂,S(O)—(CH₂)₁₋₂, S(O)₂—(CH₂)₁₋₂, (CH₂)₁₋₂—S(O), or (CH₂)₁₋₂—S(O)₂; and allother variables are as originally defined in the second class or asdefined in any of the preceding subclasses of the second class.

A third class of the present invention (Class C3) includes compounds ofFormula IIIa, IIIb, IIIc, and IIId and pharmaceutically acceptable saltsthereof:

wherein:

-   bond    in the ring is a single bond or a double bond;-   R² and R³ are each independently H or C₁₋₄ alkyl;-   R⁴ is:    -   (1) H,    -   (2) C₁₋₄ alkyl, or    -   (3) C₁₋₄ alkyl substituted with OH or OC(O)R^(A);-   R^(5a) is H, C₁₋₄ alkyl, OH or -HetR;-   R^(9a) is H or C₁₋₄ alkyl;-   alternatively, R^(5a) and R^(9a) together form oxo;-   R^(5b) is H, C₁₋₄ alkyl, or OH;-   R^(9b) is H or C₁₋₄ alkyl;-   R^(5c) is H, C₁₋₄ alkyl, or C₁₋₄ alkyl substituted with OH;-   R^(9c) is H or C₁₋₄ alkyl;-   alternatively, R^(5c) and R^(9c) together form ═CH₂;-   with the proviso that when one of R^(5a), R^(5b) and R^(5c) is other    than H or C₁₋₄ alkyl, then the other two of R^(5a), R^(5b) and    R^(5c) is H or C₁₋₄ alkyl;-   one of R⁶ and R⁷ is H, C₁₋₄ alkyl, or C₁₋₄ alkyl substituted with    OH, and the other of R⁶ and R⁷ is H or C₁₋₄ alkyl;-   R⁸ is:    -   (1) H,    -   (2) C₁₋₄ alkyl,    -   (3) C₁₋₄ haloalkyl,    -   (4) C₁₋₄ alkyl substituted with OH, O—C₁₋₄ alkyl, N(R^(A))R^(B),        C(O)N(R^(A))R^(B), C(O)R^(A), CO₂R^(A), S(O)R^(A), SO₂R^(A),        SO₂N(R^(A))R^(B), N(R^(A))C(O)R^(B), N(R^(A))SO₂R^(B), or        OC(O)R^(A),    -   (5) C₁₋₄ alkylene-HetC, or    -   (6) C₁₋₄ alkylene-HetR;-   HetC is a 5- or 6-membered heteroaromatic ring containing a total of    from 1 to 3 heteroatoms independently selected from 1 to 3 N atoms,    from zero to 1 O atom, and from zero to 1 S atom, wherein the    heteroaromatic ring is optionally substituted with 1 or 2    substituents each of which is independently C₁₋₄ alkyl, OH, O—C₁₋₄    alkyl, halogen, CN, C(O)N(R^(A))R^(B), C(O)R^(A), C(O)OR^(A), or    SO₂R^(A);-   HetR is a 5- or 6-membered saturated heterocyclic ring containing a    total of from 1 to 2 heteroatoms selected from 1 to 2 N atoms, zero    to 1 O atom, and zero to 1 S atom, wherein the S atom is optionally    S(O) or SO₂, wherein the saturated heterocyclic ring is optionally    substituted with from 1 to 2 substituents each of which is    independently C₁₋₄ alkyl, oxo, C(O)N(R^(A))R^(B), C(O)R^(A),    CO₂R^(A), or SO₂R^(A);-   each R^(A) is independently H or C₁₋₄ alkyl;-   each R^(B) is independently H or C₁₋₄ alkyl; and-   V¹, V² and V³ are as defined in Embodiment E10.

As an example of the proviso for R^(5a), R^(5b) and R^(5c) in Class C3,when R^(5a) is OH or -HetR or when R^(5a) and R^(9a) together form oxo,then R^(5b) and R^(5c) are each independently H or C₁₋₄ alkyl.

A fourth class of the present invention (Class C4) includes compounds ofFormula IIIa′ and IIId′ and pharmaceutically acceptable salts thereof:

wherein:

-   bond    in the ring is a single bond or a double bond;-   n is an integer equal to zero, 1, 2 or 3;-   V¹ and V² are each independently:    -   (1) H,    -   (2) C₁₋₄ alkyl,    -   (3) OH,    -   (4) O—C₁₋₄ alkyl,    -   (5) C₁₋₄ haloalkyl,    -   (6) O—C₁₋₄ haloalkyl,    -   (7) halogen,    -   (8) CN,    -   (9) N(R^(A))R^(B),    -   (10) C(O)N(R^(A))R^(B),    -   (11) C(O)R^(A),    -   (12) C(O)OR^(A),    -   (13) SR^(A),    -   (14) S(O)R^(A),    -   (15) SO₂R^(A),    -   (16) N(R^(A))SO₂R^(B),    -   (17) N(R^(A))SO₂N(R^(A))R^(B),    -   (18) N(R^(A))C(O)R^(B),    -   (19) N(R^(A))C(O)C(O)N(R^(A))R^(B),    -   (20) HetD,    -   (21) HetZ, or    -   (22) C(O)-HetZ,        -   wherein            -   HetD is a 5- or 6-membered heteroaromatic ring                containing a total of from 1 to 3 heteroatoms                independently selected from 1 to 3 N atoms, from zero to                1 O atom, and from zero to 1 S atom, wherein the                heteroaromatic ring is optionally substituted with 1 or                2 substituents each of which is independently C₁₋₄                alkyl, OH, O—C₁₋₄ alkyl, halogen, CN, C(O)N(R^(A))R^(B),                C(O)R^(A), C(O)OR^(A), or SO₂R^(A),            -   HetZ is a 5- or 6-membered saturated heterocyclic ring                containing a total of from 1 to 2 heteroatoms selected                from 1 to 2 N atoms, zero to 1 O atom, and zero to 1 S                atom, wherein the S atom is optionally S(O) or SO₂,                wherein the saturated heterocyclic ring is optionally                substituted with from 1 to 2 substituents each of which                is independently C₁₋₄ alkyl, oxo, C(O)N(R^(A))R^(B),                C(O)R^(A), CO₂R^(A), or SO₂R^(A),            -   and with the proviso that when HetZ is attached to the                rest of the compound via the C(O) moiety, then HetZ is                attached to the C(O) via a ring N atom;                or alternatively V¹ and V² are respectively located on                adjacent carbons in the phenyl ring and together form                methylenedioxy or ethylenedioxy;-   V³ is:    -   (1) H,    -   (2) C₁₋₄ alkyl,    -   (3) O—C₁₋₄ alkyl,    -   (4) C₁₋₄ haloalkyl,    -   (5) O—C₁₋₄ haloalkyl, or    -   (6) halogen;-   W is O, NH, N—C₁₋₄ alkyl, NC(O)—C₁₋₄ alkyl, N—C(O)O—C₁₋₄ alkyl, or    N—SO₂—C₁₋₄ alkyl;-   R² and R³ are each independently H or C₁₋₄ alkyl;-   R⁶ and R⁷ are each independently H or C₁₋₄ alkyl;-   each R^(A) is independently H or C₁₋₄ alkyl; and-   each R^(B) is independently H or C₁₋₄ alkyl.

A subclass of the fourth class (Subclass SC4-1) includes compounds ofFormula IIIa′ and IIId′, and pharmaceutically acceptable salts thereof,wherein:

-   bond    in the ring is a single bond;-   n is an integer equal to 1, 2 or 3;-   V¹ and V² are each independently:    -   (1) H,    -   (2) C₁₋₄ alkyl,    -   (3) C₁₋₄ haloalkyl,    -   (4) OH,    -   (5) O—C₁₋₄ alkyl,    -   (6) halogen,    -   (7) CN,    -   (8) C(O)NH₂,    -   (9) C(O)NH(C₁₋₄ alkyl),    -   (10) C(O)N(C₁₋₄ alkyl)₂, or    -   (11) SO₂—C₁₋₄ alkyl;        or alternatively V¹ and V² are respectively located on adjacent        carbons in the phenyl ring and together form methylenedioxy or        ethylenedioxy; and-   V³ is H, halogen, C₁₋₄ alkyl, or O—C₁₋₄ alkyl;    and all other variables are as originally defined in the Class C4.

A fifth class of the present invention (Class C5) includes compounds ofFormula IIIa′ and IIId′ and pharmaceutically acceptable salts thereof,wherein:

-   bond    in the ring is a single bond;-   n is an integer equal to 1, 2 or 3;-   V¹ and V² are each independently:    -   (1) H,    -   (2) CH₃,    -   (3) CF₃,    -   (4) OH,    -   (5) OCH₃,    -   (6) Cl, Br, or F,    -   (7) CN,    -   (8) C(O)NH₂,    -   (9) C(O)NH(CH₃),    -   (10) C(O)N(CH₃)₂, or    -   (11) SO₂CH₃;-   V³ is H, Cl, Br, F, CH₃, or OCH₃;-   W is O, NH, or N—CH₃;-   R² and R³ are both H; and-   R⁶ and R⁷ are each independently H or CH₃.

A sixth class of the present invention (Class C6) includes compounds ofFormula IIIa, IIIb, IIIc and IIId and pharmaceutically acceptable saltsthereof, wherein:

-   bond    in the ring is a single bond;-   R² and R³ are each independently H or CH₃;-   R⁴ is:    -   (1) H,    -   (2) CH₃,    -   (3) CH₂CH₃,    -   (4) CH₂CH₂CH₃,    -   (5) CH(CH₃)₂,    -   (3) (CH₂)₁₋₃—OH, or    -   (4) (CH₂)₁₋₃—OC(O)R^(A);-   R^(5a) is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, OH or -HetR;-   R^(9a) is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, or CH(CH₃)₂;-   alternatively, R^(5a) and R^(9a) together form oxo;-   R^(5b) is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, or OH;-   R^(9b) is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, or CH(CH₃)₂;-   R^(5c) is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂, or (CH₂)₁₋₃—OH;-   R^(9c) is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, or CH(CH₃)₂;-   alternatively, R^(5c) and R^(9c) together form ═CH₂;-   with the proviso that when one of R^(5a), R^(5b) and R^(5c) is other    than H, CH₃, CH₂CH₃, CH₂CH₂CH₃, or CH(CH₃)₂, then the other two of    R^(5a), R^(5b) and R^(5c) is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, or CH(CH₃)₂;-   one of R⁶ and R⁷ is H, CH₃, CH₂CH₃, CH₂CH₂CH₃, CH(CH₃)₂ or    (CH₂)₁₋₃—OH, and the other of R⁶ and R⁷ is H or CH₃;-   R⁸ is:    -   (1) H,    -   (2) CH₃,    -   (3) CH₂CH₃,    -   (4) CH₂CH₂CH₃,    -   (5) CH(CH₃)₂,    -   (6) CH₂CH₂CH₂CH₃,    -   (7) C(CH₃)₃,    -   (8) CH₂CH(CH₃)₂,    -   (9) CH(CH₃)CH₂CH₃,    -   (10) CF₃,    -   (11) CH₂CF₃,    -   (12) (CH₂)₂₋₄—U, wherein U is OH, OCH₃, N(R^(A))R^(B),        N(R^(A))C(O)R^(B), N(R^(A))SO₂R^(B), or OC(O)R^(A),    -   (13) (CH₂)₁₋₄—V, wherein V is C(O)N(R^(A))R^(B), C(O)R^(A),        CO₂R^(A), S(O)R^(A), SO₂R^(A), or SO₂N(R^(A))R^(B),    -   (14) (CH₂)₂₋₄-HetC, or    -   (15) (CH₂)₂₋₄-HetR;-   HetC is a 5-membered heteroaromatic ring selected from the group    consisting of:

-   HetR is a 5- or 6-membered saturated heterocyclic ring selected from    the group consisting of:

-   the asterisk * in HetC and HetR denotes the point of attachment to    the rest of the molecule;-   each R^(A) is independently H or CH₃;-   each R^(B) is independently H or CH₃;-   V¹ and V² are each independently:    -   (1) H,    -   (2) CH₃,    -   (3) CF₃,    -   (4) OH,    -   (5) OCH₃,    -   (6) Cl, Br, or F,    -   (7) CN,    -   (8) C(O)NH₂,    -   (9) C(O)NH(CH₃),    -   (10) C(O)N(CH₃)₂, or    -   (11) SO₂CH₃; and-   V³ is H, Cl, Br, F, CH₃, or OCH₃.

Another embodiment of the present invention is a compound, or apharmaceutically acceptable salt thereof, selected from the groupconsisting of the compounds set forth in Examples 1 to 64. Anotherembodiment of the present invention is a compound, or a pharmaceuticallyacceptable salt thereof, selected from the group consisting of thecompounds set forth in Examples 1 to 9. Another embodiment of thepresent invention is a compound, or a pharmaceutically acceptable saltthereof, selected from the group consisting of the compounds set forthin Examples 10 to 64.

Another embodiment of the present invention is a compound of Formula I,or a pharmaceutically acceptable salt thereof, as originally defined oras defined in any of the foregoing embodiments, classes, subclasses,aspects, or features, wherein the compound or its salt is substantiallypure. As used herein “substantially pure” means that the compound or itssalt is present (e.g., in a product isolated from a chemical reaction ora metabolic process) in an amount of at least about 90 wt. % (e.g., fromabout 95 wt. % to 100 wt. %), preferably at least about 95 wt. % (e.g.,from about 98 wt. % to 100 wt. %), more preferably at least about 99 wt.%, and most preferably 100 wt. %. The level of purity of the compoundsand salts can be determined using standard methods of analysis. Acompound or salt of 100% purity can alternatively be described as onewhich is free of detectable impurities as determined by one or morestandard methods of analysis. With respect to a compound of theinvention which has one or more asymmetric centers and can occur asmixtures of stereoisomers, a substantially pure compound can be either asubstantially pure mixture of the stereoisomers or a substantially pureindividual diastereomer or enantiomer.

Other embodiments of the present invention include the following:

(a) A pharmaceutical composition comprising an effective amount of acompound of Formula I and a pharmaceutically acceptable carrier.

(b) A pharmaceutical composition which comprises the product prepared bycombining (e.g., mixing) an effective amount of a compound of Formula Iand a pharmaceutically acceptable carrier.

(c) The pharmaceutical composition of (a) or (b), further comprising aneffective amount of an anti-HIV agent selected from the group consistingof HIV antiviral agents, immunomodulators, and anti-infective agents.

(d) The pharmaceutical composition of (c), wherein the anti-HIV agent isan antiviral selected from the group consisting of HIV proteaseinhibitors, non-nucleoside HIV reverse transcriptase inhibitors, andnucleoside HIV reverse transcriptase inhibitors.

(e) A pharmaceutical combination which is (i) a compound of Formula Iand (ii) an anti-HIV agent selected from the group consisting of HIVantiviral agents, immunomodulators, and anti-infective agents; whereinthe compound of Formula I and the anti-HIV agent are each employed in anamount that renders the combination effective for the inhibition of HIVintegrase, for the treatment or prophylaxis of infection by HIV, or forthe treatment, prophylaxis or delay in the onset of AIDS.

(f) The combination of (e), wherein the anti-HIV agent is an antiviralselected from the group consisting of HIV protease inhibitors,non-nucleoside HIV reverse transcriptase inhibitors and nucleoside HIVreverse transcriptase inhibitors.

(g) A method of inhibiting HIV integrase in a subject in need thereofwhich comprises administering to the subject an effective amount of acompound of Formula I.

(h) A method for the treatment or prophylaxis of infection by HIV in asubject in need thereof which comprises administering to the subject aneffective amount of a compound of Formula I.

(i) The method of (h), wherein the compound of Formula I is administeredin combination with an effective amount of at least one antiviralselected from the group consisting of HIV protease inhibitors,non-nucleoside HIV reverse transcriptase inhibitors, and nucleoside HIVreverse transcriptase inhibitors.

(j) A method for the treatment, prophylaxis, or delay in the onset ofAIDS in a subject in need thereof which comprises administering to thesubject an effective amount of a compound of Formula I.

(k) The method of (j), wherein the compound is administered incombination with an effective amount of at least one antiviral selectedfrom the group consisting of HIV protease inhibitors, non-nucleoside HIVreverse transcriptase inhibitors, and nucleoside HIV reversetranscriptase inhibitors.

(l) A method of inhibiting HIV integrase in a subject in need thereofwhich comprises administering to the subject the pharmaceuticalcomposition of (a), (b), (c) or (d) or the combination of (e) or (f).

(m) A method for the treatment or prophylaxis of infection by HIV in asubject in need thereof which comprises administering to the subject thepharmaceutical composition of (a), (b), (c) or (d) or the combination of(e) or (f).

(n) A method for the treatment, prophylaxis, or delay in the onset ofAIDS in a subject in need thereof which comprises administering to thesubject the pharmaceutical composition of (a), (b), (c) or (d) or thecombination of (e) or (f).

The present invention also includes a compound of the present invention(i) for use in, (ii) for use as a medicament for, or (iii) for use inthe preparation of a medicament for: (a) the inhibition of HIVintegrase, (b) treatment or prophylaxis of infection by HIV, or (c)treatment, prophylaxis, or delay in the onset of AIDS. In these uses,the compounds of the present invention can optionally be employed incombination with one or more anti-HIV agents selected from HIV antiviralagents, anti-infective agents, and immunomodulators.

Additional embodiments of the invention include the pharmaceuticalcompositions, combinations and methods set forth in (a)-(n) above andthe uses set forth in the preceding paragraph, wherein the compound ofthe present invention employed therein is a compound of one of theembodiments, aspects, classes, subclasses, or features of the compoundsdescribed above. In all of these embodiments, the compound mayoptionally be used in the form of a pharmaceutically acceptable salt.

The present invention also includes prodrugs of the compounds of FormulaI. The term “prodrug” refers to a derivative of a compound of Formula I,or a pharmaceutically acceptable salt thereof, which is converted invivo into Compound I. Prodrugs of compounds of Formula I can exhibitenhanced solubility, absorption, and/or lipophilicity compared to thecompounds per se, thereby resulting in increased bioavailability andefficacy. The in vivo conversion of the prodrug can be the result of anenzyme-catalyzed chemical reaction, a metabolic chemical reaction,and/or a spontaneous chemical reaction (e.g., solvolysis). The prodrugcan be, for example, a derivative of a hydroxy group such as an ester(—OC(O)R), a carbonate ester (—OC(O)OR), a phosphate ester(—O—P(═O)(OH)₂), or an ether (—OR). Other examples include thefollowing: When the compound of Formula I contains a carboxylic acidgroup, the prodrug can be an ester or an amide, and when the compound ofFormula I contains a primary amino group, the prodrug can be an amide,carbamate, imine, or a Mannich base. One or more functional groups inCompound I can be derivatized to provide a prodrug thereof. Conventionalprocedures for the selection and preparation of suitable prodrugderivatives are described, for example, in Design of Prodrugs, edited byH. Bundgaard, Elsevier, 1985; C. S. Larsen and J. Ostergaard, “Designand application of prodrugs” in: Textbook of Drug Design and Discovery,3^(rd) edition, edited by C. S. Larsen, 2002, pp. 410-458; and Beaumontet al., Current Drug Metabolism 2003, vol. 4, pp. 461-458; thedisclosures of each of which are incorporated herein by reference intheir entireties. Prodrugs of compounds of Formula I can also beselected and prepared by application of the descriptions in WO2005/070901 and WO 2005/117904, both herein incorporated by reference intheir entireties.

As used herein, the term “alkyl” refers to any linear or branched chainalkyl group having a number of carbon atoms in the specified range.Thus, for example, “C₁₋₆ alkyl” (or “C₁-C₆ alkyl”) refers to all of thehexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- andt-butyl, n- and isopropyl, ethyl and methyl. As another example, “C₁₋₄alkyl” refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl andmethyl.

The term “alkylene” refers to any divalent linear or branched chainaliphatic hydrocarbon radical (or alternatively an “alkanediyl”) havinga number of carbon atoms in the specified range. Thus, for example,“—C₁₋₆ alkylene-” refers to any of the C₁ to C₆ linear or branchedalkylenes. A class of alkylenes of particular interest with respect tothe invention is —(CH₂)₁₋₆—, and subclasses of particular interestinclude —(CH₂)₁₋₄—, —(CH₂)₁₋₃—, —(CH₂)₁₋₂—, and —CH₂—. Also of interestis the alkylene —CH(CH₃)—.

The term “C(O)” refers to carbonyl. The terms “S(O)₂” and “SO₂” eachrefer to sulfonyl. The term “S(O)” refers to sulfinyl.

The symbols “*” and

at the end of a bond each refer to the point of attachment of afunctional group or other chemical moiety to the rest of the molecule ofwhich it is a part.

The terms “cycloalkyl” refers to any cyclic ring of an alkane having anumber of carbon atoms in the specified range. Thus, for example, “C₃₋₈cycloalkyl” (or “C₃-C₈ cycloalkyl”) refers to cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The term “halogen” (or “halo”) refers to fluorine, chlorine, bromine andiodine (alternatively referred to as fluoro, chloro, bromo, and iodo).

The term “haloalkyl” refers to an alkyl group as defined above in whichone or more of the hydrogen atoms has been replaced with a halogen(i.e., F, Cl, Br and/or I). Thus, for example, “C₁₋₆ haloalkyl” (or“C₁-C₆ haloalkyl”) refers to a C₁ to C₆ linear or branched alkyl groupas defined above with one or more halogen substituents. The term“fluoroalkyl” has an analogous meaning except that the halogensubstituents are restricted to fluoro. Suitable fluoroalkyls include theseries (CH₂)₀₋₄CF₃ (i.e., trifluoromethyl, 2,2,2-trifluoroethyl,3,3,3-trifluoro-n-propyl, etc.).

Unless expressly stated to the contrary, all ranges cited herein areinclusive. For example, a heterocyclic ring described as containing from“1 to 4 heteroatoms” means the ring can contain 1, 2, 3 or 4heteroatoms. It is also to be understood that any range cited hereinincludes within its scope all of the sub-ranges within that range. Thus,for example, a heterocyclic ring described as containing from “1 to 4heteroatoms” is intended to include as aspects thereof, heterocyclicrings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2heteroatoms, and so forth. As another example, an aryl or heteroaryldescribed as optionally substituted with “from 1 to 5 substituents” isintended to include as aspects thereof, an aryl or heteroaryl optionallysubstituted with 1 to 4 substituents, 1 to 3 substituents, 1 to 2substituents, 2 to 5 substituents, 2 to 4 substituents, 2 to 3substituents, 3 to 5 substituents, 3 to 4 substituents, 1 substituent, 2substituents, 3 substituents, 4 substituents, and 5 substituents.

When any variable (e.g., R^(A), R^(B), or AryD) occurs more than onetime in any constituent or in Formula I or in any other formuladepicting and describing compounds of the invention, its definition oneach occurrence is independent of its definition at every otheroccurrence. Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

It is understood that the right side of a group Y is attached to R^(K)and the left side of a group Y is attached to the rest of the molecule.Thus, for example, for Y=C₁₋₆ alkylene-C(O) (e.g., (CH₂)₁₋₂—C(O)), R^(K)is attached to the carbonyl; i.e., C₁₋₆ alkylene-C(O)—R^(K) (e.g.,(CH₂)₁₋₂—C(O)—R^(K)). Similarly, it is understood that the right side ofa group Z is attached to R^(L) and the left side of a group Z isattached to ring A. Thus, for example, for Z=C₁₋₆ alkylene-C(O) (e.g.,(CH₂)₁₋₂—C(O)), R^(L) is attached to the carbonyl; i.e., C₁₋₆alkylene-C(O)—R^(L) (e.g., (CH₂)₁₋₂—C(O)—R^(L)).

The term “substituted” (e.g., as in “is optionally substituted with from1 to 5 substituents . . . ”) includes mono- and poly-substitution by anamed substituent to the extent such single and multiple substitution(including multiple substitution at the same site) is chemicallyallowed. Unless expressly stated to the contrary, substitution by anamed substituent is permitted on any atom in a ring (e.g., aryl, aheteroaromatic ring, or a saturated heterocyclic ring) provided suchring substitution is chemically allowed and results in a stablecompound.

Any of the various carbocyclic and heterocyclic rings and ring systemsdefined herein may be attached to the rest of the compound at any ringatom (i.e., any carbon atom or any heteroatom) provided that a stablecompound results.

A “stable” compound is a compound which can be prepared and isolated andwhose structure and properties remain or can be caused to remainessentially unchanged for a period of time sufficient to allow use ofthe compound for the purposes described herein (e.g., therapeutic orprophylactic administration to a subject).

As a result of the selection of substituents and substituent patterns,certain of the compounds of the present invention can have asymmetriccenters and can occur as mixtures of stereoisomers, or as individualdiastereomers or enantiomers. All isomeric forms of these compounds,whether isolated or in mixtures, are within the scope of the presentinvention.

As would be recognized by one of ordinary skill in the art, certain ofthe compounds of the present invention can exist as tautomers. Alltautomeric forms of these compounds, whether isolated or in mixtures,are within the scope of the present invention.

In instances where a hydroxy (—OH) substituent is permitted on aheteroaromatic ring and keto-enol tautomerism is possible, it isunderstood that the substituent might in fact be present, in whole or inpart, in the keto form, as exemplified here for a hydroxypyridinylsubstituent:

Compounds of the present invention having a hydroxy substituent on acarbon atom of a heteroaromatic ring are understood to include compoundsin which only the hydroxy is present, compounds in which only thetautomeric keto form (i.e., an oxo substitutent) is present, andcompounds in which the keto and enol forms are both present.

Certain of the compounds of the present invention can exhibit achirality resulting from the presence of bulky substituents that hinderthe otherwise free rotation about a bond. These rotational enantiomersare named atropisomers, and the interconversion can be sufficiently slowto allow for their separation and characterization. See, e.g., J. March,Advanced Organic Chemistry, 4th Edition, John Wiley & Sons, 1992, pp.101-102; and Ahmed et al., Tetrahedron 1998, 13277. For example, certainof the compounds of the present invention as exemplified with structuresA and B below in which there could be sufficient hindrance to rotationalong the bond indicated with an arrow to permit separation of theenantiomers using, e.g., column chromatography on a chiral stationaryphase. The present invention includes atropisomers of compounds embracedby Formula I, singly and in mixtures.

The compounds of the present inventions are useful in the inhibition ofHIV integrase (e.g., HIV-1 integrase), the prophylaxis or treatment ofinfection by HIV and the prophylaxis, treatment or the delay in theonset of consequent pathological conditions such as AIDS. Theprophylaxis of AIDS, treating AIDS, delaying the onset of AIDS, theprophylaxis of infection by HIV, or treating infection by HIV is definedas including, but not limited to, treatment of a wide range of states ofHIV infection: AIDS, ARC (AIDS related complex), both symptomatic andasymptomatic, and actual or potential exposure to HIV. For example, thecompounds of this invention are useful in treating infection by HIVafter suspected past exposure to HIV by such means as blood transfusion,exchange of body fluids, bites, accidental needle stick, or exposure topatient blood during surgery.

The compounds of this invention are useful in the preparation andexecution of screening assays for antiviral compounds. For example, thecompounds of this invention are useful for isolating enzyme mutants,which are excellent screening tools for more powerful antiviralcompounds. Furthermore, the compounds of this invention are useful inestablishing or determining the binding site of other antivirals to HIVintegrase, e.g., by competitive inhibition. Thus the compounds of thisinvention can be commercial products to be sold for these purposes.

The compounds of the present invention can be administered in the formof pharmaceutically acceptable salts. The term “pharmaceuticallyacceptable salt” refers to a salt which possesses the effectiveness ofthe parent compound and which is not biologically or otherwiseundesirable (e.g., is neither toxic nor otherwise deleterious to therecipient thereof). Suitable salts include acid addition salts whichmay, for example, be formed by mixing a solution of the compound of thepresent invention with a solution of a pharmaceutically acceptable acidsuch as hydrochloric acid, sulfuric acid, acetic acid, trifluoroaceticacid, or benzoic acid. Certain compounds of the invention carry anacidic moiety, in which case suitable pharmaceutically acceptable saltsthereof can include alkali metal salts (e.g., sodium or potassiumsalts), alkaline earth metal salts (e.g., calcium or magnesium salts),and salts formed with suitable organic ligands such as quaternaryammonium salts. Also, in the case of an acid (—COOH) or alcohol groupbeing present, pharmaceutically acceptable esters can be employed tomodify the solubility or hydrolysis characteristics of the compound.

The term “administration” and variants thereof (e.g., “administered” or“administering”) in reference to a compound of the invention meanproviding the compound or a prodrug of the compound to the individual inneed of treatment or prophylaxis. When a compound of the invention or aprodrug thereof is provided in combination with one or more other activeagents (e.g., antiviral agents useful for the prophylaxis or treatmentof HIV infection or AIDS), “administration” and its variants are eachunderstood to include provision of the compound or prodrug and otheragents at the same time or at different times. When the agents of acombination are administered at the same time, they can be administeredtogether in a single composition or they can be administered separately.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients, as well as any productwhich results, directly or indirectly, from combining the specifiedingredients.

By “pharmaceutically acceptable” is meant that the ingredients of thepharmaceutical composition must be compatible with each other and notdeleterious to the recipient thereof.

The term “subject” (or, alternatively, “patient”) as used herein refersto an animal, preferably a mammal, most preferably a human, who has beenthe object of treatment, observation or experiment.

The term “effective amount” as used herein means that amount of activecompound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal or human that is beingsought by a researcher, veterinarian, medical doctor or other clinician.In one embodiment, the effective amount is a “therapeutically effectiveamount” for the alleviation of the symptoms of the disease or conditionbeing treated. In another embodiment, the effective amount is a“prophylactically effective amount” for prophylaxis of the symptoms ofthe disease or condition being prevented. The term also includes hereinthe amount of active compound sufficient to inhibit HIV integrase andthereby elicit the response being sought (i.e., an “inhibition effectiveamount”). When the active compound (i.e., active ingredient) isadministered as the salt, references to the amount of active ingredientare to the free acid or free base form of the compound.

For the purpose of the inhibition of HIV integrase, the prophylaxis ortreatment of HIV infection, or the prophylaxis or treatment or delay inthe onset of AIDS, the compounds of the present invention, optionally inthe form of a salt, can be administered by any means that producescontact of the active agent with the agent's site of action. They can beadministered by any conventional means available for use in conjunctionwith pharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents. They can be administered alone, buttypically are administered with a pharmaceutical carrier selected on thebasis of the chosen route of administration and standard pharmaceuticalpractice. The compounds of the invention can, for example, beadministered orally, parenterally (including subcutaneous injections,intravenous, intramuscular, intrasternal injection or infusiontechniques), by inhalation spray, or rectally, in the form of a unitdosage of a pharmaceutical composition containing an effective amount ofthe compound and conventional non-toxic pharmaceutically-acceptablecarriers, adjuvants and vehicles. Liquid preparations suitable for oraladministration (e.g., suspensions, syrups, elixirs and the like) can beprepared according to techniques known in the art and can employ any ofthe usual media such as water, glycols, oils, alcohols and the like.Solid preparations suitable for oral administration (e.g., powders,pills, capsules and tablets) can be prepared according to techniquesknown in the art and can employ such solid excipients as starches,sugars, kaolin, lubricants, binders, disintegrating agents and the like.Parenteral compositions can be prepared according to techniques known inthe art and typically employ sterile water as a carrier and optionallyother ingredients, such as a solubility aid. Injectable solutions can beprepared according to methods known in the art wherein the carriercomprises a saline solution, a glucose solution or a solution containinga mixture of saline and glucose. Further description of methods suitablefor use in preparing pharmaceutical compositions of the presentinvention and of ingredients suitable for use in said compositions isprovided in Remington's Pharmaceutical Sciences, 18^(th) edition, editedby A. R. Gennaro, Mack Publishing Co., 1990 and in Remington—The Scienceand Practice of Pharmacy, 21^(st) edition, Lippincott Williams &Wilkins, 2005.

The compounds of this invention can be administered orally in a dosagerange of about 0.001 to about 1000 mg/kg of mammal (e.g., human) bodyweight per day in a single dose or in divided doses. One preferreddosage range is about 0.01 to about 500 mg/kg body weight per day orallyin a single dose or in divided doses. Another preferred dosage range isabout 0.1 to about 100 mg/kg body weight per day orally in single ordivided doses. For oral administration, the compositions can be providedin the form of tablets or capsules containing about 1.0 to about 500milligrams of the active ingredient, particularly 1, 5, 10, 15, 20, 25,50, 75, 100, 150, 200, 250, 300, 400, and 500 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patientto be treated. The specific dose level and frequency of dosage for anyparticular patient may be varied and will depend upon a variety offactors including the activity of the specific compound employed, themetabolic stability and length of action of that compound, the age, bodyweight, general health, sex, diet, mode and time of administration, rateof excretion, drug combination, the severity of the particularcondition, and the host undergoing therapy.

As noted above, the present invention is also directed to use of the HIVintegrase inhibitor compounds of the present invention with one or moreanti-HIV agents useful in the treatment of HIV infection or AIDS. An“anti-HIV agent” is any agent which is directly or indirectly effectivein the inhibition of HIV integrase or another enzyme required for HIVreplication or infection, the treatment or prophylaxis of HIV infection,and/or the treatment, prophylaxis or delay in the onset of AIDS. It isunderstood that an anti-HIV agent is effective in treating, preventing,or delaying the onset of HIV infection or AIDS and/or diseases orconditions arising therefrom or associated therewith. For example, thecompounds of this invention may be effectively administered, whether atperiods of pre-exposure and/or post-exposure, in combination witheffective amounts of one or more HIV antivirals, immunomodulators,antiinfectives, or vaccines useful for treating HIV infection or AIDS,such as those disclosed in Table 1 of WO 01/38332 or in the Table in WO02/30930. Suitable HIV antivirals for use in combination with thecompounds of the present invention include, for example, HIV proteaseinhibitors (e.g., indinavir, atazanavir, lopinavir optionally withritonavir, saquinavir, or nelfinavir), nucleoside HIV reversetranscriptase inhibitors (e.g., abacavir, lamivudine (3TC), zidovudine(AZT), or tenofovir), and non-nucleoside HIV reverse transcriptaseinhibitors (e.g., efavirenz or nevirapine). It will be understood thatthe scope of combinations of the compounds of this invention with HIVantivirals, immunomodulators, anti-infectives or vaccines is not limitedto the foregoing substances or to the list in the above-referencedTables in WO 01/38332 and WO 02/30930, but includes in principle anycombination with any pharmaceutical composition useful for the treatmentof HIV infection or AIDS. The HIV antivirals and other agents willtypically be employed in these combinations in their conventional dosageranges and regimens as reported in the art, including, for example, thedosages described in the Physicians' Desk Reference, 58^(th) edition,Thomson P D R, 2004, or the 59^(th) edition thereof, 2005. The dosageranges for a compound of the invention in these combinations are thesame as those set forth above. It is understood that pharmaceuticallyacceptable salts of the compounds of the invention and/or the otheragents (e.g., indinavir sulfate) can be used as well.

Abbreviations employed herein include the following: AcOH=acetic acid;BOC or Boc=t-butyloxycarbonyl;BOP=benzotriazol-1-yloxytris-(dimethylamino)phosphonium; Bu=butyl;DIPEA=diisopropylethylamine (or Hunig's base);DMF=N,N-dimethylformamide; DMSO=dimethylsulfoxide;dppa=diphenylphosphoryl azide; EDC orEDAC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; ES MS=electrospraymass spectroscopy; Et=ethyl; EtOAc=ethyl acetate;HOAT=1-hydroxy-7-azabenzotriazole; HPLC=high performance liquidchromatography; LDA=lithium diisopropylamide; LHMDS=lithiumhexamethyldisilazide; Me=methyl; MeOH=methanol; MTBE=methyl tert-butylether; NaHMDS=sodium hexamethyldisilazide; NMR=nuclear magneticresonance; TEA=triethylamine; TFA=trifluoroacetic acid;THF=tetrahydrofuran.

The compounds of the present invention can be readily prepared accordingto the following reaction schemes and examples, or modificationsthereof, using readily available starting materials, reagents andconventional synthesis procedures. In these reactions, it is alsopossible to make use of variants which are themselves known to those ofordinary skill in this art, but are not mentioned in greater detail.Furthermore, other methods for preparing compounds of the invention willbe readily apparent to the person of ordinary skill in the art in lightof the following reaction schemes and examples. Unless otherwiseindicated, all variables are as defined above.

Scheme 1 depicts a method for preparing5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate intermediates usefulfor making compounds of the present invention. In Part A of the scheme,lactam 1-1 can be alkylated with an appropriate alkyl halide in thepresence of a deprotonating agent (e.g., NaH, NaHMDS, or LHMDS) to give1-2, using methods as described in Jerry March, Advanced OrganicChemistry, 3rd edition, John Wiley & Sons, 1985, pp. 377-379.Piperidin-2-one 1-2 can be converted to the correspondingdihydropyridinone compound 1-5 following the two step procedure setforth in Meyers et al., Tet. Lett. 1995, 36: 7051-7054, wherein thelactam can be treated with base (e.g., LHMDS, LDA or Na HMDS) and methylbenzene sulfinate to give intermediate 1-4, which can then be treated byheating in a high boiling solvent (e.g., toluene or xylenes) andoptionally in the presence of base (e.g., Na₂CO₃ or K₂CO₃) to effect theelimination to 1-5. Separately, as shown in Part B of Scheme 1, oxazolesof the type 1-9 can readily be prepared by acylating amino acid ester1-6 with an oxalate ester 1-7 in the presence of base (e.g., tertiaryamines such as TEA, DIPEA, or pyridine) to afford acylated compound 1-8,which can then be cyclized and dehydrated (using a dehydrating agentsuch as P₂O₅) in the manner described in Krapcho et al. J. HeterocyclicChem. 1995, 32, 1693-1702 to afford oxazole 1-9. Diels-Alder reaction of1-9 and 1-5, optionally in the presence of water or an acid (e.g., AcOHor TFA) (preferably in the presence of water as described in “Catalysisof Diels-Alder Reactions in Water and in Hydrogen-Bonding Environments”,Wittkopp, A. & Schreiner, P. R. in: Chemistry of Dienes and Polyenes,2000, Vol. 2, John Wiley & Sons, pp. 1029-1088), will then provide thedesired napthyridine intermediate 1-10.

Scheme 2 depicts a method for preparing naphthyridine carboxylates andcarboxamides embraced by the present invention from naphthyridineintermediate 1-10, wherein the intermediate 1-10 can be treated with asuitable oxidizing agent (e.g., hydrogen peroxide or m-chloroperbenzoicacid) as described in Sharpless et al., J. Org. Chem. 1998, 1740 andCaron et al., Tet. Letters 2000, 2299 and references cited therein toobtain N-oxide 2-1, which can then be treated as described in Suzuki etal., J. Med. Chem. 1992, 35, 4045-4053 with acetic anhydride to effectthe rearrangement to the O-acylated intermediate, and then treated witha nucleophile (e.g., an alkoxide such as NaOMe) to afford the desireddioxohexahydro-2,6-naphthyridine-1-carboxylate 2-2. In the preparationof compounds of the present invention that require the protection ofphenolic hydroxyl group on 2-2, the intermediate 1-10 can be treatedwith trimethylsilyldiazomethane to provide the O-methyl etherselectively. Chemical transformations similar to those described in theconversion of 1-10 to 2-2 provided 2-5, which can be deprotected to givethe desired phenol.

Scheme 3 depicts a method for preparingdiazocino[2,1-a]-2,6-naphthyridines 3-3 and 3-4 (n=4) anddiazepino[2,1-a]-2,6-naphthyridines 3-3 and 3-4 (n=3) embraced by thepresent invention from naphthyridine intermediate 2-2, wherein theintermediate 2-2 is treated with a suitable base (e.g., magnesiumalkoxide) and a suitable dihaloalkane (e.g., 1-bromo-4-chlorobutane or1-bromo-3-chloropropane) to provide the alkylated intermediate 3-1.Treatment of halide 3-1 with a primary amine in the presence or absenceof an iodide catalyst such as potassium iodide or tetra-n-butylammoniumiodide provided the aminoester intermediate 3-2. Base catalyzedhydrolysis of the amino-ester 3-2 provided the corresponding amino acidwhich was treated with an amide coupling reagent such as EDC or BOP toprovide the tricyclic napthyridine products 3-3. The R^(Y) substituenton 3-3 can be removed under appropriate conditions to provide products3-4.

Scheme 4 depicts a method for preparingpyrazino[2,1-a]-2,6-naphthyridines 4-1 and 4-2 embraced by the presentinvention from naphthyridine intermediate 2-2, wherein the intermediate2-2 is treated with a suitable base (e.g., magnesium alkoxide, cesiumcarbonate, or potassium carbonate) and an appropriately protectedα-amino-β-haloalkane (e.g., a protected 1-amino-2-haloethane such astert-butyl (2-bromoethyl)carbamate) to provide the tricyclicnapthyridine products 4-1. Treatment of 4-1 with a suitable base andalkylating reagent (e.g., an alkyl halide) affords 4-2.

Scheme 5 depicts a method for preparingoxazino[2,1-a]-2,6-naphthyridines 5-1 embraced by the present inventionfrom naphthyridine intermediate 2-2, wherein the intermediate 2-2 istreated with a suitable base (e.g., magnesium alkoxide, cesiumcarbonate, or potassium carbonate) and a suitable α,β-dihaloalkane(e.g., a dihaloethane such as 1-bromo-2-chloroethane) to provide thetricyclic napthyridine products 5-1. Oxazepino and oxazocino analogs canbe similarly prepared using a suitable dihaloalkane such asBr—CH₂CH₂CH₂—Cl or Br—CH₂CH₂CH₂CH₂—Cl.

Scheme 6 depicts a method for preparingimidazo[2,1-a]-2,6-naphthyridines 6-4 and 6-5 embraced by the presentinvention from naphthyridine intermediate 2-2, wherein the intermediate2-2 is treated with a suitable base (e.g., magnesium alkoxide, cesiumcarbonate, or potassium carbonate) and a suitable substituted alkylhaloacetate (e.g., tert-butyl bromoacetate) to provide the alkylationproduct 6-1. Selective hydrolysis provides the naphthyridine carboxylicacid 6-2, which can be converted to the corresponding tert-butylcarbamate 6-3 via a Curtius rearrangement in the manner described in J.March, Advanced Organic Chemistry, 3rd edition, John Wiley & Sons, 1992,p. 1091 (e.g., acid 6-2 can be treated with diphenylphosphoryl azide inthe presence of anhydrous tert-butanol to afford carbamate 6-3).Carbamate 6-3 can then be treated with acid (e.g., HCl or TFA) in amanner similar to the conditions described in T. W. Greene & P. G. M.Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley &Sons, 1999, to provide the tricyclic naphthyridine derivative 6-4.Treatment of 6-4 with a suitable alkylating agent (e.g., an alkylhalide, an alkyl bromoacetate, or a benzyloxyalkyl halide) in thepresence of base (e.g., NaH, NaHMDS, LHMDS, or LDA) affords product 6-5.Further conventional functional group interconversion on the R″ sidechain can provide additional compounds of the present invention.

Scheme 7 depicts a method for preparing3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione7-3 from naphthyridine intermediate 2-5, wherein the intermediate 2-5 istreated with a suitable substituted aminoalcohol and an amide couplingreagent (e.g., EDC or BOP) to provide the amide product 7-1. Sequentialtreatment of 7-1 with alkyl or aryl sulfonic anhydride (e.g.,methanesulfonic anhydride) followed by a suitable base (e.g., cesiumcarbonate) provides the tricyclic naphthyridine derivative 7-2. Furtherstandard functional group interconversion on the side chains R^(a) toR^(g) and removal of the methyl ether protecting group provided thetargeted inhibitors 7-3.

Scheme 8 depicts a method for preparingoxazino[2,1-a]-2,6-naphthyridines from naphthyridine intermediate 2-2,wherein the intermediate 2-2 is treated with a suitable base (e.g.,magnesium alkoxide, cesium carbonate, or potassium carbonate) and asuitable allyl halide (e.g., allyl bromide) to provide the allylatednapthyridine product 8-1. Osmium tetroxide-catalyzed dihydroxylation ofthe terminal olefin (VanRheenen et. al. Tet. Lett. 1973, 1976) followedby intramolecular cyclization provides the intermediateoxazinonaphthyridine 8-2. Deprotection of the methyl ether protectinggroup on 8-2 provides the target compound 8-3.

In the methods for preparing compounds of the present invention setforth in the foregoing schemes, functional groups in various moietiesand substituents (in addition to those already explicitly noted in theforegoing schemes) may be sensitive or reactive under the reactionconditions employed and/or in the presence of the reagents employed.Such sensitivity/reactivity can interfere with the progress of thedesired reaction to reduce the yield of the desired product, or possiblyeven preclude its formation. Accordingly, it may be necessary ordesirable to protect sensitive or reactive groups on any of themolecules concerned. Protection can be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973 and in T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 3^(rd) edition, 1999, and 2^(nd) edition, 1991. Theprotecting groups may be removed at a convenient subsequent stage usingmethods known in the art. Alternatively the interfering group can beintroduced into the molecule subsequent to the reaction step of concern.

The following examples serve only to illustrate the invention and itspractice. The examples are not to be construed as limitations on thescope or spirit of the invention.

EXAMPLE 111-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

Step 1: 1-(3-Chloro-4-fluorobenzyl)piperidin-2-one

To a cold (0° C.) solution of valerolactam (153.30 g, 1.54 mol) inanhydrous 1-methyl-2-pyrrolidinone (3.5 L), sodium hydride (67.7 g, 1.69mol, 60% dispersion in oil) was added over a period of 5 minutes. Thereaction mixture was stirred for 30 minutes, and a solution of3-chloro-4-fluorobenzylbromide (345.5 g, 1.54 mol) in1-methyl-2-pyrrolidinone (200 mL) was added over 30 minutes at 0° C. Thereaction mixture was stirred at 0° C. for 1 hour, and was allowed towarm up and stirred at room temperature overnight. The reaction mixturewas quenched with distilled water (5 L), and extracted withdichloromethane (three times; 2 L, 1 L, 1 L). The organic extracts werecombined, washed with water (3×; 4 L each time). The residual oil wasdissolved in ethyl acetate (4 L), and extracted with water (3×; 2 L eachtime). The organic layer was separated, concentrated under vacuum togive the title product that solidified upon standing.

¹H NMR (400 MHz, CDCl₃) δ 7.24 (m, 2H), 7.0 (m, 2H), 7.1 (m, 1H), 4.56(s, 2H), 3.19 (t, J=4.9 Hz, 2H), 2.46 (t, J=6.4 Hz, 2H), 1.8-1.75 (m,4H).

Step 2: 1-(3-Chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one

To a cold (−20° C.) solution of1-(3-chloro-4-fluorobenzyl)piperidin-2-one (340 g, 1.41 mol) inanhydrous tetrahydrofuran (5 L) under an atmosphere of nitrogen, asolution of lithium bis(trimethylsilyl)amide (3.09 L, 3.09 mol; 1M inTHF) was added over a period of 40 minutes with the temperature of thereaction maintained at −20° C. After the addition was complete, thereaction mixture was stirred at −20° C. for one hour. Methyl benzenesulfonate (231 mL, 1.69 mol) was added to the reaction mixture over aperiod of 30 minutes. The reaction mixture was stirred at −20° C. for 30minutes. The product mixture was diluted with ethyl acetate (4 L) andwashed with water (four times; 2 L each time). The organic extract wasconcentrated under vacuum. The residue was dissolved in toluene (4 L),treated with solid sodium carbonate (500 g), and heated at 100° C. forone hour. The product mixture was diluted with ethyl acetate (4 L) andwashed with water (4 times; 2 L each). The organic extract wasconcentrated under vacuum. The residue was subjected to columnchromatography on silica gel eluting with a gradient of 0-60% EtOAc inheptanes. Collection and concentration of appropriate fractions providethe title compound as oil.

¹H NMR (400 MHz, CDCl₃) δ 7.3 (m, 1H), 7.15 (m, 1H), 7.1 (t, 1H), 6.6(m, 1H), 6.0 (m, 1H), 4.55 (s, 2H), 3.33 (t, 2H), 1.38 (m, 2H). ES MSM+1=240.13

Step 3: 2-Butoxy-2-oxoethanaminium chloride

To a suspension of glycine hydrochloride (400 g, 3.58 mol) in n-butanol(8 L), thionyl chloride (1.37 L, 18.84 mol) was added slowly dropwise.After addition was complete, the reaction was heated at 70° C.overnight. The product mixture was concentrated under vacuum and theresidue was triturated with a mixture of heptane/ethyl acetate. Thewhite solid precipitated was filtered and dried under a stream of drynitrogen to provide the title compound.

¹H NMR (400 MHz, CDCl₃) δ 8.5 (br s, 3H), 4.18 (t, J=6.7 Hz, 2H), 4.0(br s, 2H), 1.62 (m, 2H), 1.38 (m, 2H), 0.92 (t, J=7.4 Hz, 3H). ES MSM+1=132.

Step 4: Butyl N-[ethoxy(oxo)acetyl]glycinate

A mixture of 2-butoxy-2-oxoethanaminium chloride (573.5 g, 3.42 mol),triethylamine (415 g, 4.1 mol), and diethyl oxalate (1.0 kg, 6.8 mol) inethanol (7 L) was heated at 50° C. for 3 hours. The product mixture wascooled and concentrated under vacuum. The residue was dissolved inmethylene chloride and washed with two 4 L portions of water. Theorganic fraction was dried over anhydrous magnesium sulfate, filtered,and concentrated under vacuum. The residual oil was subjected to columnchromatography on silica gel eluting with heptanes/ethyl acetategradient. Collection and concentration of appropriate fractions providedthe title material.

¹H NMR (400 MHz, CDCl₃) δ 7.56 (br s, 1H), 4.37 (q, J=7.2 Hz, 2H), 4.2(t, J=6.6 Hz, 2H), 4.12 (d, J=5.5 Hz, 2H), 1.64 (p, J=6.8 Hz, 2H), 1.39(t, J=7.15 Hz, 3H), 1.37 (m, 2H), 0.94 (t, J=7.4 Hz, 3H). ES MS M+1=232.

Step 5: Ethyl 5-butoxy-1,3-oxazole-2-carboxylate

To a solution of butyl N-[ethoxy(oxo)acetyl]glycinate (783 g, 3.38 mol)in acetonitrile (8 L) in a 50 L glass reactor with overhead stirrer,phosphorus pentoxide (415 g, 2.92 mol) was added in portions. Thereaction was heated at 60° C. for 1 hour. The product mixture wascooled, and water (8 L) was added with the mixture maintained at 20° C.The resultant mixture was extracted with dichloromethane (8 L, and 3times 2 L). The organic extracts were combined, washed twice withsaturated aqueous sodium bicarbonate (8 L total), dried over anhydrousmagnesium sulfate, filtered and concentrated under vacuum. The residualoil was subjected to column chromatography on silica gel eluting with0-30% heptanes/ethyl acetate gradient. Collection and concentration ofappropriate fractions provided the title material.

¹H NMR (400 MHz, CDCl₃) δ 6.33 (s, 1H), 4.42 (q, J=7.2 Hz, 2H), 4.18 (t,J=6.4 Hz, 2H), 1.8 (p, J=6.4 Hz, 2H), 1.47 (p, J=7.4 Hz, 2H), 1.41 (t,J=7.15 Hz, 3H), 0.97 (t, J=7.4 Hz, 3H). ES MS M+1=214.

Step 6: Ethyl6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate

A mixture of ethyl 5-butoxy-1,3-oxazole-2-carboxylate (44.5 g, 208.6mol), 1-(3-chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one (25 g,104.3 mol), and water (2.82 mL, 156.7 mol) was heated in a sealed heavywalled vessel at 130° C. with stirring for 72 hours. Upon cooling, theproduct mixture solidified. The solid was triturated with diethyl etherand collected by filtration. The product was further purified bycrystallization from boiling ethyl acetate.

¹H NMR (400 MHz, CDCl₃) δ 12.79 (s, 1H), 8.42 (s, 1H), 7.4 (dd, J=2, 7Hz, 1H), 7.2 (m, 1H), 7.15 (t, J=8.6 Hz, 1H), 4.7 (s, 2H), 4.4 (q, J=7Hz, 2H), 3.5 (m, 4H), 1.4 (t, J=7 Hz, 3H). ES MS M+1=379.0

Step 7: Ethyl6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate2-oxide

A mixture of ethyl6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate(22 g, 58 mol), glacial acetic acid (500 mL), and hydrogen peroxide(65.8 mL, 30% by weight in water) was heated at 100° C. for four hours.The resultant solution was cooled in an ice bath to 25° C. and treatedwith saturated aqueous sodium sulfite solution while keeping thereaction mixture below 40° C. When starch paper test showed completeconsumption of residual peroxide, the solution was concentrated to twothird of its volume, pH was adjusted to ˜3 with aqueous HCl and thesolution was extracted with dichloromethane (3 times). The organicextracts were combined, dried over anhydrous sodium sulfate, filteredand concentrated under vacuum to afford the title product as oil.

¹H NMR (400 MHz, CDCl₃) δ 12.65 (s, 1H), 7.9 (s, 1H), 7.38 (dd, J=2, 7Hz, 1H), 7.27-7.1 (m, 2H), 4.66 (s, 2H), 4.44 (q, J=7 Hz, 2H), 3.52 (t,J=7 Hz, 2H), 2.90 (t, J=7 Hz, 2H), 1.38 (t, J=7 Hz, 3H). ES MS M+1=395.0

Step 8: Ethyl3,4-bis(acetyloxy)-6-(3-chloro-4-fluorobenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate

A solution of ethyl6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate2-oxide (23 g, 58 mol) in acetic anhydride (400 mL) was heated undernitrogen at 100° C. for one hour. The product mixture was concentratedunder vacuum to the title bisacetate and was used in the following stepwithout further purification.

¹H NMR (400 MHz, CDCl₃) δ 7.36 (m, 1H), 7.2-7.1 (m, 1H), 7.12 (t, J=8Hz, 1H), 4.68 (br s, 2H), 4.4 (q, J=7 Hz, 2H), 3.48 (m, 2H), 3.35 (m,2H), 2.38 (br s, 6H), 1.4 (t, J=7 Hz, 3H). ES MS M+1=394.9

Step 9: Methyl6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate

A solution of ethyl3,4-bis(acetyloxy)-6-(3-chloro-4-fluorobenzyl)-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate(27.8 g, 58 mmol) and sodium methoxide (41.8 mL, 232 mmol; 30% by weightsolution of NaOMe in MeOH) in anhydrous methanol (300 mL) was heated at40° C. for 5 hours. The volume of the reaction mixture was reduced by ahalf under vacuum, diluted with anhydrous tetrahydrofuran (400 mL), andtreated with an additional solution of sodium methoxide in methanol (33mL). The reaction mixture was stirred at room temperature overnight andthen warmed to 50° C. for four hours. The product mixture was acidifiedwith dilute hydrochloric acid to pH 3 and extracted with chloroformseveral times. The organic extracts were combined, dried over anhydroussodium sulfate, filtered, and concentrated under vacuum to provide thetitle compound as oil.

¹H NMR (400 MHz, CDCl₃) δ 10.0-8.2 (br s, 1H), 7.38 (dd, J=6.8. 2 Hz,1H), 7.2 (m, 1H), 7.13 (t, J=8.4 Hz, 1H), 4.68 (s, 2H), 3.92 (s, 3H),3.46 (t, J=6.4 Hz, 2H), 3.34 (t, J=6.4 Hz, 2H). ES MS M+1=380.9

Step 10: Methyl2-(4-chlorobutyl)-6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate

A mixture of6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide(0.80 g, 2.19 mmol) and magnesium methoxide in methanol (10.6 mL, 6-10%methanol solution available from Aldrich) in DMSO (22 mL) was heated at60° C. for one hour. Methanol was exhaustively removed under vacuum over45 minutes. The resulting DMSO solution was treated with1-bromo-4-chlorobutane (1.80 g, 10.50 mmol) and stirred at 60° C. underan atmosphere of nitrogen for one hour. The reaction mixture was dilutedwith ethyl acetate and washed with dilute hydrochloric acid. The organicextract was washed with 10% aqueous potassium carbonate, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was triturated with diethyl ether. The solid precipitated wascollected by filtration to provide the title compound. ES MS M+1=471

Step 11: Methyl6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-[4-(methylamino)butyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate

A mixture of methyl2-(4-chlorobutyl)-6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate(0.10 g, 0.21 mmol), methylamine in tetrahydrofuran (1 mL, 2M), andtetra-n-butylammonium iodide in tetrahydrofuran (5 mL) was heated at 60°C. for 3 days. The reaction mixture was concentrated under vacuum. Theresidue was partitioned between dichloromethane and saturated aqueoussodium bicarbonate. The organic extract was washed with brine, driedover anhydrous sodium sulfate, filtered, and concentrated under vacuumto provide the title compound. This was used in the following stepwithout further purification.

ES MS M+1=466

Step 12:6-(3-Chloro-4-fluorobenzyl)-4-hydroxy-2-[4-(methylamino)butyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylicacid

Methyl6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-[4-(methylamino)butyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate(0.18 g, 0.38 mmol) and potassium hydroxide (0.17 g, 2.3 mmol) in amixture of 1:1:1 v/v/v tetrahydrofuran-methanol-water (4.5 mL) washeated at 50° C. overnight. The reaction mixture was concentrated undervacuum. The residue was partitioned between dichloromethane and dilutehydrochloric acid. The aqueous extract was concentrated under vacuum toprovide the title compound as hydrochloride salt. This was used in thefollowing step without further purification. ES MS M+1=452

Step 13:11-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

A solution of6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-[4-(methylamino)butyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylicacid (0.18 g, 0.40 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.08 g, 0.41 mmol), and 1-hydroxy-7-azabenzotriazole(0.07 g, 0.51 mmol), and N-methylmorpholine (0.35 mL, 3.16 mmol) inanhydrous DMF (3 mL) was stirred at room temperature overnight. Thereaction mixture was concentrated under vacuum. The residue was purifiedby reverse phase high pressure liquid chromatography. Collection andconcentration of appropriate fractions provided the title compound.

¹H NMR (400 MHz, CDCl₃) δ 7.35 (br s, 1H), 7.18 (br s, 1H), 7.13 (m,1H), 4.80-4.66 (m), 4.55 (d, J=14.7 Hz, 1H), 3.97-2.98 (m), 3.12 (s,3H), 2.08-1.77 (m, 4H). ES MS exact mass M+1=434.1282

EXAMPLE 211-(4-Fluorobenzyl)-9-hydroxy-2-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

Step 1: Methyl6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-[4-(methylamino)butyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate

A mixture of methyl6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-[4-(methylamino)butyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate(0.68 g, 1.45 mmol; Example 1, Step 11) and a solution oftrimethylsilyldiazomethane in hexane (2.2 mL, 4.35 mmol; 2M) indichloromethane-methanol (1.5 & 4.5 mL) was stirred at room temperaturefor one hour. The reaction mixture was concentrated under vacuum toprovide the title compound. This was used in the following step withoutfurther purification. ES MS M+1=480

Step 2:11-(3-Chloro-4-fluorobenzyl)-9-methoxy-2-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

The titled compound was prepared in a manner similar to that describedin Example 1, steps 12 and 13, substituting methyl6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-[4-(methylamino)butyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylatewith methyl6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-[4-(methylamino)butyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate.

Step 3:11-(4-Fluorobenzyl)-9-methoxy-2-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

A mixture of11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione(52 mg, 0.12 mmol) and 10% palladium on charcoal (70 mg) in ethanol (6mL) was stirred at room temperature under a balloon of hydrogenovernight. The reaction mixture was filtered and concentrated undervacuum. ES MS M+1=480

Step 4:11-(4-Fluorobenzyl)-9-hydroxy-2-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

A solution of11-(4-fluorobenzyl)-9-methoxy-2-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione(27 mg, 0.07 mmol) in 30% hydrobromide in acetic acid was stirred atroom temperature for 30 minutes. The reaction mixture was concentratedunder vacuum. The residue was concentrated from a solution in toluenetwice. The resultant solid was triturated with a mixture of diethylether and dichloromethane to provide the title compound.

¹H NMR (400 MHz, CDCl₃) δ 7.40 (dd, J=8.4, 5.5 Hz, 2H), 7.22 (t, J=8.6Hz, 2H), 4.77 (d, J=14.7 Hz, 1H), 4.71 (d, J=14.7 Hz, 1H), 3.54-3.27(m), 3.12 (s, 3H), 2.89 (m, 1H), 2.61 (m, 1H), 2.06 (M, 1H), 1.84 (M,2H), 1.71 (M, 1H). ES MS exact mass M+1=400.1652

EXAMPLE 310-(3-Chloro-4-fluorobenzyl)-8-hydroxy-2-methyl-2,3,4,5,11,12-hexahydro[1,4]diazepino[2,1-a]-2,6-naphthyridine-1,7,9(10H)-trione

The title compound was prepared in a manner similar to that described inExample 1, substituting 1-bromo-4-chlorobutane with1-bromo-3-chloropropane in Step 10.

¹H NMR (400 MHz, CDCl₃) δ 13.40 (br s, 1H), 7.36 (dd, J=6.8, 2.0 Hz,1H), 7.20 (m, 1H), 7.13 (t, J=8.6, Hz, 1H), 5.28 (m, 1H), 4.73 (d,J=14.5 Hz, 1H), 4.60 (d, 14.5 Hz, 1H), 3.49-3.14 (m), 3.14 (s, 3H), 2.74(m, 1H), 2.10 (m, 2H). ES MS exact mass M+1=420.1122

EXAMPLE 410-(3-Chloro-4-fluorobenzyl)-8-hydroxy-2,3,4,5,11,12-hexahydro[1,4]diazepino[2,1-a]-2,6-naphthyridine-1,7,9(10H)-trione

Step 1:10-(3-Chloro-4-fluorobenzyl)-8-hydroxy-2-(4-methoxybenzyl)-2,3,4,5,11,12-hexahydro[1,4]diazepino[2,1-a]-2,6-naphthyridine-1,7,9(10H)-trione

The titled compound was prepared in a manner similar to that describedin Example 1, substituting 1-bromo-4-chlorobutane with1-bromo-3-chloropropane in Step 10, and replacing methylamine with4-methoxybenzylamine in Step 11. ES MS M+1=526

Step 2:10-(3-Chloro-4-fluorobenzyl)-8-hydroxy-2,3,4,5,11,12-hexahydro[1,4]diazepino[2,1-a]-2,6-naphthyridine-1,7,9(10H)-trione

A mixture of10-(3-chloro-4-fluorobenzyl)-8-hydroxy-2-(4-methoxybenzyl)-2,3,4,5,11,12-hexahydro[1,4]diazepino[2,1-a]-2,6-naphthyridine-1,7,9(10H)-trione(18 mg, 30 μmol) and p-toluenesulfonic acid (26 mg, 0.14 mmol) intoluene (0.5 mL) was heated at 110° C. for 8 hours. The reaction mixturewas concentrated under vacuum. The residue was purified by reverse phasehigh pressure liquid chromatography. Collection and lyophilization ofappropriate fractions provided the title compound.

¹H NMR (400 MHz, CD₃CD) δ 7.50 (dd, J=7.0, 2.2 Hz, 1H), 7.34 (m, 1H),7.23 (t, J=8.8, Hz, 1H), 5.13 (br s, 1H), 4.85 (br s, 2H), 3.13-2.78(m), 3.29 (s, 3H), 2.03 (br s, 3H). ES MS exact mass M+1=406.0980

EXAMPLE 59-(3-Chloro-4-fluorobenzyl)-7-hydroxy-3,4,10,11-tetrahydro-2-H-pyrazino[2,1-a]-2,6-naphthyridine-1,6,8(9H)-trione

A mixture of6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide(1.00 g, 2.63 mmol; Example 1, Step 9) and magnesium methoxide inmethanol (13.1 mL, 6-10% methanol solution available from Aldrich) inDMSO (26 mL) was heated at 60° C. for one hour. Methanol wasexhaustively removed under vacuum over 45 minutes. The resulting DMSOsolution was treated with tort-butyl (2-bromoethyl)carbamate (2.94 g,13.13 mmol) and stirred at 60° C. under an atmosphere of nitrogen forone hour. The reaction mixture was diluted with ethyl acetate and washedsuccessively with 10% sodium thiosulfate and brine. The organic extractwas dried over anhydrous sodium sulfate, filtered, and concentratedunder vacuum. The residue was purified by reverse phase high pressureliquid chromatography. Collection and lyophilization of appropriatefractions provided the title compound.

¹H NMR (400 MHz, CDCl₃) δ 14.00 (s, 1H), 7.36 (dd, J=7.0, 2.2 Hz, 1H),7.21 (m, 1H), 7.14 (t, J=8.8, Hz, 1H), 6.07 (br s, 1H), 4.68 (s, 2H),4.35 (t, 2H), 3.25 (t, 2H), 3.43 (t, 2H), 3.46 (t, 2H). ES MS exact massM+1=392.0789

EXAMPLE 69-(3-Chloro-4-fluorobenzyl)-7-hydroxy-2-methyl-3,4,10,11-tetrahydro-2-H-pyrazino[2,1-a]-2,6-naphthyridine-1,6,8(9H)-trione

A mixture of9-(3-chloro-4-fluorobenzyl)-7-hydroxy-3,4,10,11-tetrahydro-2-H-pyrazino[2,1-a]-2,6-naphthyridine-1,6,8(9H)-trione(53 mg, 0.14 mmol; Example 5), and sodium hydride (12.3 mg; 60%dispersion in oil) in DMF (2 mL) was stirred at 0° C. for 20 minutes. Tothe resultant solution, methyl iodide (96 mg, 0.68 mmol) was added andthe reaction mixture was heated at 40° C. for four hours. The reactionmixture was quenched with methanol and concentrated under vacuum. Theresidue was purified by reverse phase high pressure liquidchromatography. Collection and lyophilization of appropriate fractionsprovided the title compound.

¹H NMR (400 MHz, CDCl₃) δ 7.37 (dd, J=6.8, 2.0 Hz, 1H), 7.20 (m, 1H),7.14 (t, J=8.6, Hz, 1H), 4.68 (s, 2H), 4.35 (t, J=5.3 Hz, 2H), 3.61 (t,J=5.3 Hz, 2H), 3.43 (m, 4H), 3.14 (s, 3H). ES MS exact mass M+1=406.0963

EXAMPLE 79-(3-Chloro-4-fluorobenzyl)-7-hydroxy-3,4,10,11-tetrahydro[1,4]oxazino[3,4-a]-2,6-naphthyridine-1,6,8(9H)-trione

A mixture of6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide(0.15 g, 0.39 mmol; Example 1, Step 9) and magnesium methoxide inmethanol (2 mL, 6-10% methanol solution available from Aldrich) in DMSO(4 mL) was heated at 60° C. for 30 minutes. Methanol was exhaustivelyremoved under vacuum over 45 minutes. The resultant DMSO solution wastreated with 1-bromo-2-chloroethane (0.28 g, 1.97 mmol) and stirred at60° C. under an atmosphere of nitrogen overnight. The reaction mixturewas diluted with ethyl acetate and dilute hydrochloric acid. The organicextract was washed with aqueous sodium sulfite, brine, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum. Theresidue was purified by reverse phase high pressure liquidchromatography. Collection and lyophilization of appropriate fractionsprovided the title compound, which was recrystallized from a mixture ofethyl acetate and hexane

¹H NMR (400 MHz, CDCl₃) δ 7.38 (dd, J=6.5, 2.5 Hz, 1H), 7.21 (m, 1H),7.15 (t, J=8.8, Hz, 1H), 4.69 (s, 2H), 4.55 (br s), 4.36 (br s), 3.96(br s), 3.52 (t, 2H), 3.48 (t, 2H). ES MS exact mass M+1=393.0652

EXAMPLE 88-(3-Chloro-4-fluorobenzyl)-6-hydroxy-1,3-dimethyl-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine-2,5,7(3H)-trione

Step 1: Methyl2-(2-tert-butoxy-2-oxoethyl)-6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate

A mixture of6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide(0.50 g, 1.31 mmol; Example 1, Step 9) and magnesium methoxide inmethanol (6.6 mL, 6-10% methanol solution available from Aldrich) inDMSO (13 mL) was heated at 60° C. for one hour. Methanol wasexhaustively removed under vacuum over 45 minutes. The resultant DMSOsolution was treated with tert-butyl bromoacetate (1.80 g, 10.50 mmol)and stirred at 50° C. under an atmosphere of nitrogen for one hour. Thereaction mixture was diluted with ethyl acetate and washed with ice colddilute hydrochloric acid. The organic extract was washed with aqueoussodium thiosulfate, brine, dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The residue was triturated witha mixture of diethyl ether and ethyl acetate. The solid precipitated wascollected by filtration to provide the title compound. ES MS M+1=495

Step 2: Methyl2-(2-tert-butoxy-2-oxoethyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate

A mixture of methyl2-(2-tert-butoxy-2-oxoethyl)-6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate(0.70 g, 1.41 mmol) and a solution of trimethylsilyldiazomethane inhexane (1.0 mL, 2.0 mmol; 2M) in dichloromethane-methanol (4 & 2 mL) wasstirred at room temperature overnight. The reaction mixture wasconcentrated under vacuum. The residue was subject to columnchromatography on silica gel eluting with 2% methanol indichloromethane. Collection and concentration of appropriate fractionsprovided the title compound. ES MS M+1=509

Step 3:2-(2-tert-Butoxy-2-oxoethyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylicacid

A mixture of methyl2-(2-tert-butoxy-2-oxoethyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate(0.49 g, 0.96 mmol) and lithium hydroxide monohydrate (0.12 g, 2.9 mmol)in a mixture of tetrahydrofuran (3 mL) and water (2 mL) was stirred atroom temperature for one hour. The reaction mixture was concentratedunder vacuum. The residue was partitioned between dichloromethane anddilute hydrochloric acid. The organic extract was dried over anhydroussodium sulfate, filtered, and concentrated under vacuum to provide thetitle compound. This was used in the following step without furtherpurification. ES MS M+1=495

Step 4:1-[(tert-Butyloxycarbonyl)amino]-2-(2-tert-butoxy-2-oxoethyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine

A mixture of2-(2-tert-butoxy-2-oxoethyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylicacid (0.31 g, 0.62 mmol), triethylamine (0.10 mL, 0.74 mmol), anddiphenylphosphoryl azide (0.19 g, 0.69 mmol) in a mixture of anhydrousdioxane (6 mL) and anhydrous tert-butanol (6 mL) was heated at 90° C.overnight. The reaction mixture was concentrated under vacuum. Theresidue was subject to column chromatography on silica gel. Collectionand concentration of appropriate fractions provided the title compound.ES MS M+1=566

Step 5:8-(3-Chloro-4-fluorobenzyl)-6-methoxy-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine-2,5,6(3H)-trione

A mixture of1-[(tert-butylcarbonyl)amino]-2-(2-tert-butoxy-2-oxoethyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine(0.11 g, 0.96 mmol) and hydrogen chloride in dioxane (5 mL, 4 M) wasstirred at room temperature for four hours. The reaction mixture wasconcentrated under vacuum to provide the title compound. This was usedin the following step without further purification. ¹H NMR (400 MHz,CD₃OD) δ 7.60 (dd, J=7.0, 2.0 Hz, 1H), 7.30 (m, 1H), 7.19 (t, J=8.6, Hz,1H), 5.44 (s, 1H), 4.83 (s, 2H), 4.72 (s, 2H), 3.90 (s, 3H), 3.51 (t,J=5.8 Hz, 2H), 2.63 (t, J=5.8 Hz, 2H) ES MS M+1=392

Step 6:8-(3-Chloro-4-fluorobenzyl)-6-methoxy-1,3-dimethyl-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine-2,5,6(3H)-trione

A mixture of8-(3-chloro-4-fluorobenzyl)-6-methoxy-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine-2,5,6(3H)-trione(67 mg, 0.17 mmol), sodium hydride (17 mg, 60% dispersion; 0.42 mmol),iodomethane (49 mg, 0.35 mmol) in anhydrous DMF (8 mL) was stirred atroom temperature overnight. The reaction mixture was concentrated undervacuum. The residue was subject to column chromatography on silica gel.Collection and concentration of appropriate fractions provided the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ 7.39 (dd, J=6.8, 2.0 Hz, 1H), 7.23(m, 1H), 7.12 (t, J=8.6, Hz, 1H), 4.74 (t, J=14.8 Hz, 1H), 4.72 (q,J=6.9 Hz, 1H), 4.63 (t, J=14.8 Hz, 1H), 4.05 (s, 3H), 3.41 (m, 2H), 3.39(s, 3H), 2.92 (m, 2H), 1.74 (d, J=6.9 Hz, 3H). ES MS M+1=420

Step 7:8-(3-Chloro-4-fluorobenzyl)-6-hydroxy-1,3-dimethyl-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine-2,5,7(3H)-trione

A mixture of8-(3-chloro-4-fluorobenzyl)-6-methoxy-1,3-dimethyl-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine-2,5,6(3H)-trione(10 mg, 23 μmol) and 33% hydrogen bromide in acetic acid (1 mL) wasstirred at room temperature for two hours. The reaction mixture wasconcentrated under vacuum. The residue was triturated with diethyl etherand filtered to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ7.38 (dd, J=6.8, 2.0 Hz, 1H), 7.23 (m, 1H), 7.12 (t, J=8.6, Hz, 1H),4.71 (br signals, 3H), 3.47 (br signals, 2H), 3.40 (br, s, 3H), 3.12 (brs, 2H), 1.76 (br signals, 3H) ES MS exact mass M+1=406.0969

EXAMPLE 98-(3-Chloro-4-fluorobenzyl)-6-hydroxy-1,3,3-trimethyl-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine-2,5,7(3H)-trione

The titled compound was prepared in a manner similar to that describedin Example 8. In Step 6, additional sodium hydride and methyl iodidewere added for trimethylation. ¹H NMR (400 MHz, CDCl₃) δ 7.36 (dd,J=6.8, 2.0 Hz, 1H), 7.23 (m, 1H), 7.16 (t, J=8.6, Hz, 1H), 4.69 (br s,3H), 3.48 (br signals, 2H), 3.40 (s, 3H), 3.10 (br s, 2H), 1.79 (br s,6H) ES MS exact mass M+1=420.1112

EXAMPLE 1011-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-[2-(acetyloxy)ethyl]-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

Step 1: Ethyl6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate

A mixture of ethyl 5-butoxy-1,3-oxazole-2-carboxylate (248 g, 1.16 mol;Example 1, step 5),1-(3-chloro-4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one (199.2 g, 0.83mol; Example 1, step 2), and deionized water (22.5 mL, 1.25 mol) in aglass lined stainless steel high pressure reactor (with the interstitialspace between the liner and the pressure vessel was filled with water)was heated at 135° C. with stirring for 72 hours. The product mixturewas cooled in an ice-water bath and the gaseous by-product was carefullyvented. The orange solid product was triturated with methyl tert-butylether (300 mL) and collected by filtration. The product recrystallizedfrom boiling ethanol-water (˜500 mL, 9:1 v/v), collected by filtration,washed successively with a small quantity of ethanol, methyl tert-butylether (300 mL), and heptane (200 mL), and air dried to afford the titlecompound.

¹H NMR (400 MHz, CDCl₃) δ 12.79 (s, 1H), 8.42 (s, 1H), 7.4 (dd, J=2, 7Hz, 1H), 7.2 (m, 1H), 7.15 (t, J=8.6 Hz, 1H), 4.7 (s, 2H), 4.4 (q, J=7Hz, 2H), 3.5 (m, 4H), 1.4 (t, J=7 Hz, 3H). (ES MS M+1=379.0)

Step 2: Ethyl6-(3-chloro-4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate

To a stirred solution of ethyl6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate(208 g, 0.55 mol) in a mixture of dichloromethane (830 mL) and methanol(410 mL) at 10° C., a solution of (trimethyl-silyl)diazomethane (600 mL,1.2 mol; 2M) in hexanes was added over a period of 1 hour with thereaction temperature maintained below 15° C. The reaction mixture(unstirred) was allowed to stand at 10° C. overnight, and then at 20° C.for additional 4 hours. The reaction mixture was cooled back to 10° C.and quenched with acetic acid (˜75 mL). The product mixture wasconcentrated under vacuum and the residue recrystallized from boilingmethyl tert-butyl ether and heptane. The solid recrystallized wascollected by filtration, washed with a mixture of methyl tert-butylether and heptane (1:1, v/v), and air dried to afford the titlecompound.

¹H NMR (400 MHz, CDCl₃) δ 8.42 (s, 1H), 7.41 (dd, J=2, 7 Hz, 1H), 7.24(m, 1H), 7.11 (t, J=8.6 Hz, 1H), 4.70 (s, 2H), 4.42 (q, J=7 Hz, 2H),4.12 (s, 3H), 3.4 (m, 4H), 1.42 (t, J=7 Hz, 3H). (ES MS M+1=392.9)

Step 3: Ethyl3-(acetyloxy)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate

To a cold (5° C.) mixture of ethyl6-(3-chloro-4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate(199 g, 0.51 mol) and urea hydrogen peroxide (100 g, 1.06 mol) indichloromethane (1.5 L), trifluoroacetic anhydride was added dropwiseover a period of 45 minutes. The resultant homogeneous solution wasstirred at 20° C. for 30 minutes and cooled back to 5° C. The reactionmixture was treated with aqueous potassium hydrogen phosphate (pH ofaqueous extract increased to ˜8), followed by slow addition of freshlyprepared aqueous sodium bisulfite solution with the temperature of theproduct mixture maintained below 25° C. The organic extract wasseparated and the aqueous fraction extracted with toluene (2×). Theorganic extracts were combined, dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. Without further purification, asolution of this intermediate N-oxide (˜280 g) and acetic anhydride (239mL, 2.5 mol) in toluene (2 L) was heated at 110° C. for 16 hours. Theproduct mixture was concentrated under vacuum. The resultant oil wasconcentrated from toluene (300 mL, twice) and stored under vacuumovernight. The acetate product was used in the following step withoutfurther purification.

(ES MS M+1=408.9)

Step 4:6-(3-Chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylicacid

A mixture of ethyl3-(acetyloxy)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate(217 g, 0.48 mol), lithium hydroxide monohydrate (70.7 g, 1.67 mol), andwater (320 mL) in ethanol (1.8 L) was sonicated for 20 minutes. Thereaction mixture was cooled in an ice-water bath and treated withhydrochloric acid (425 mL, 3 M). The resultant light yellow solid wasfiltered, washed successively with water (1 L), a 3:2 v/v mixture ofwater and ethanol (500 mL), MTBE (750 mL), and air dried. The yellowsolid was dissolved in anhydrous DMF (700 mL) and concentrated undervacuum. The procedure was repeated twice to remove residual water. Theyellow solid was triturated with MTBE, filtered, and stored under vacuumovernight to afford the title acid.

¹H NMR (400 MHz, CDCl₃) δ 7.54 (dd, J=2, 7 Hz, 1H), 7.3 (m, 2H), 4.65(s, 2H), 3.89 (s, 3H), 3.43 (t, J=5.5 Hz, 2H), 3.00 (t, J=5.5 Hz, 2H).(ES MS M+1=380.9)

Step 5:N-[2-(Benzyloxy)ethyl]-4-{[tert-butyl(dimethyl)silyl]oxy}butan-1-amine

A mixture of 4-hydroxybutylamine (4.0 g, 44.9 mmol),tert-butyldimethyl-silyl chloride (7.4 g, 49.3 mmol) and imidazole (6.7g, 98.7 mmol) in dichloromethane (150 mL) was stirred at roomtemperature for 2 hours. The product mixture was washed successivelywith aqueous NaHCO₃, water, and brine. The organic extract was driedover anhydrous sodium sulfate, filtered, and concentrated under vacuum.This intermediate silylated aminoalcohol was used without furtherpurification. To a mixture of the amine (1.0 g, 4.9 mmol) andbenzyloxyacetaldehyde (0.74 g, 4.9 mmol) in dichloroethane (15 mL) atroom temperature, sodium triacetoxyborohydride (1.3 g, 6.3 mmol) wasadded. The reaction mixture was concentrated under vacuum. The residuewas partitioned between ethyl acetate and aqueous sodium carbonate. Theorganic extract was dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was subjected to columnchromatography on silica gel eluting with 2% methanol indichloromethane. Collection and concentration of appropriate fractionsafforded the title silyloxybutyl-amine.

¹H NMR (400 MHz, CDCl₃) δ 7.33-7.25 (m, 5H), 4.51 (s, 2H), 3.60 (m, 4H),2.79 (br t, J=4.9 Hz, 2H), 2.60 (br t, 2H), 1.52 (br signal, 5H), 0.87(s, 9H), 0.03 (s, 6H).

Step 6:N-[2-(Benzyloxy)ethyl]-N-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

A mixture of6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylicacid (0.19 g, 0.49 mmol),N-[2-(benzyloxy)-ethyl]-4-{[tert-butyl(dimethyl)silyl]oxy}butan-1-amine(0.19 g, 0.55 mmol), EDC (0.10 g, 0.55 mmol), HOAt (75 mg, 0.55 mmol)and diisopropylethylamine (0.35 mL, 1.99 mmol) in DMF (2 mL) was stirredat room temperature overnight. The product mixture was concentratedunder vacuum. The residue was partitioned between methylene chloride andwater. The organic extract was dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum to afford the title compound.This material was used in the following step without furtherpurification.

Step 7:N-[2-(Benzyloxy)ethyl]-N-(4-hydroxybutyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

To a solution ofN-[2-(benzyloxy)ethyl]-N-(4-{[tert-butyl(dimethyl)silyl]-oxy}butyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(0.41 g, 0.59 mmol) in THF, a solution of tetra-n-butyl-ammoniumfluoride (0.65 mL, 1M) in THF was added. The reaction mixture wasstirred at room temperature overnight, and concentrated under vacuum.The residue was subjected to column chromatography on silica gel elutingwith 3% methanol in dichloromethane. Collection and concentration ofappropriate fractions afforded the title compound.

Step 8:N-[2-(Benzyloxy)ethyl]-N-(4-methanesulfonyloxybutyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

To a solution ofN-[2-(benzyloxy)ethyl]-N-(4-hydroxybutyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(0.20 g, 0.34 mmol) and diisopropylethylamine (0.07 mL, 0.41 mmol) indichloromethane, methanesulfonic anhydride (71 mg, 0.41 mmol) was added.The reaction mixture was stirred at room temperature for 30 minutes. Theproduct mixture was washed with water. The organic extract was driedover anhydrous sodium sulfate, filtered, and concentrated under vacuum.The residue was subjected to column chromatography on silica gel elutingwith 0.5% methanol in dichloromethane. Collection and concentration ofappropriate fractions afforded the title compound.

¹H NMR (400 MHz, CDCl₃) mixture of rotamers δ 7.36-7.08 (m, 8H), 4.64(s, 1H), 4.57 (s, 1H), 4.50 (s, 1H), 4.33 (s, 1H). 4.06 (s, 3H), 3.75(s, 2H), 3.69 (q, J=5.7 Hz, 1H), 3.58 (t, J=7.3 Hz, 1H), 3.49 (br m,3H), 3.44 (s, 1.5H), 3.52 (s, 1.5H), 3.25 (q, J=6.8 Hz, 2H), 2.97 (t,6.4 Hz, 1H), 2.69 (q, 6.7 Hz, 2H), 1.78-1.36 (m). (ES MS M+1=664.2)

Step 9:11-(3-Chloro-4-fluorobenzyl)-9-methoxy-2-[2-(benzyloxy)ethyl]-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

To a mixture ofN-[2-(benzyloxy)ethyl]-N-(4-methanesulfonyloxybutyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide(90 mg, 0.14 mmol) and cesium carbonate (53 mg, 0.16 mmol) in DMF washeated at 75° C. for 90 minutes. The product mixture was concentratedunder vacuum. The residue was subjected to column chromatography onsilica gel eluting with 5% methanol in dichloromethane. Collection andconcentration of appropriate fractions afforded the title compound.

¹H NMR (400 MHz, CDCl₃) δ 7.34 (dd, J=2.0, 6.8 Hz, 1H), 7.27-7.08 (m),7.09 (t, J=8.6 Hz, 1H), 5.28 (s), 4.74 (dd, J=6.2, 13.9 Hz, 1H), 4.67(d, J=14.8 Hz, 1H), 4.57 (d, 14.8 Hz, 1H), 4.48 (s, 2H), 4.18 (m, 1H),4.09 (s, 3H), 3.78-3.66 (m, 2H), 3.46-3.16 (m, 6H), 2.70-2.63 (m, 1H),2.25-2.00 (m, 1H), 1.85-1.72 (m, 1H). (ES MS M+1=569.0)

Step 10:11-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-[2-(acetyloxy)ethyl]-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

A mixture of11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-[2-(benzyl-oxy)ethyl]-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione(120 mg, 0.21 mmol) and 33% hydrogen bromide in acetic acid (1 mL) indioxane (1 mL) was stirred at room temperature for 1 hour. The productmixture was concentrated under vacuum. The residue was subjected toreverse phase column chromatography on C-18 stationary phase eluted witha 95-5% water-acetonitrile gradient. Collection and lyophilization ofappropriate fractions afforded the title compound.

¹H NMR (400 MHz, CDCl₃) δ 7.34 (dd, 6.7, 1.6 Hz, 1H), 7.18 (br signal,1H), 7.12 (t, J=8.6 Hz, 1H), 4.79 (br signal), 4.76 (d, J=14.7 Hz, 1H),4.54 (d, J=14.7 Hz, 1H), 4.46 (br signal), 4.18 (m, 2H), 3.48-3.25 (m),3.00-2.93 (m), 2.61-2.57 (m), 2.03 (s, 3H), 2.09-1.75 (m). (ES MSM+1=506.2)

EXAMPLE 1111-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-(2-hydroxyethyl)-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

A mixture of11-(3-chloro-4-fluorobenzyl)-9-hydroxy-2-[2-(acetyloxy)ethyl]-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione(50 mg, 0.1 mmol) and aqueous lithium hydroxide (0.5 mL, 1M) in THF wasstirred at room temperature for 1 hour. The product mixture wasconcentrated under vacuum. The residue was subjected to reverse phasecolumn chromatography on C-18 stationary phase eluted with a 95-5%water-acetonitrile gradient. Collection and lyophilization ofappropriate fractions afforded the title compound.

¹H NMR (400 MHz, CDCl₃) δ 13.17 (br s, 1H), 7.35 (dd, J=6.9, 2.2 Hz,1H), 7.18 (br signal, 1H), 7.13 (t, J=8.4 Hz, 1H), 4.82 (m, 1H), 4.79(d, J=15.0 Hz, 1H), 4.54 (d, J=15.0 Hz, 1H), 4.19-4.13 (m, 1H),3.95-3.82 (m, 2H), 3.49-3.35 (m), 3.29-3.24 (m, 1H), 3.03-2.96 (m, 1H),2.64-2.57 (m, 1H), 2.13-0.09 (m). (ES MS M+1=464.1378)

EXAMPLE 12[11-(3-Chloro-4-fluorobenzyl)-9-hydroxy-1,8,10-trioxo-1,3,4,5,6,8,10,11,12,13-deca-hydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridin-2-yl]aceticacid

Step 1: tert-Butyl [(4-hydroxybutyl)amino]acetate

To a cold (0° C.) solution of 4-hydroxybutylamine (9.1 g, 101.8 mmol) indiethyl ether (100 mL), a solution of tert-butyl bromoacetate (7.4 g,49.3 mmol) in diethyl ether (25 mL) was added dropwise over a period of2 hours. The reaction mixture was allowed to warm up slowly to roomtemperature and stirred at the temperature overnight. The productmixture was washed successively with aqueous NaHCO₃, water, and brine.The organic extract was dried over anhydrous sodium sulfate, filtered,and concentrated under vacuum. This intermediate was used in thefollowing reaction without further purification.

¹H NMR (400 MHz, CDCl₃) δ 3.58 (t, J=5.3 Hz, 2H), 3.26 (s, 2H), 2.63 (t,J=6.1 Hz, 2H), 1.67-1.58 (m, 4H), 1.45 (s, 9H).

Step 2: tert-Butyl[11-(3-chloro-4-fluorobenzyl)-9-methoxy-1,8,10-trioxo-1,3,4,5,6,8,10,11,12,13-decahydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridin-2-yl]acetate

The title compound was prepared in a manner similar to that described inExample 10, steps 6 to 8, substitutingN-[2-(benzyloxy)ethyl]-4-{[tert-butyl(dimethyl)-silyl]oxy}butan-1-aminewith tert-butyl [(4-hydroxybutyl)amino]acetate in step 6.

¹H NMR (400 MHz, CDCl₃) δ 7.45 (dd, J=6.7, 1.6 Hz, 1H), 7.18 (br signal,1H), 7.08 (t, J=8.6 Hz, 1H), 4.75 (dd, J=13.9, 6.0 Hz, 1H), 4.67 (d,J=14.7 Hz, 1H), 4.63 (d, 14.7 Hz, 1H), 4.25 (d, J=16.8 Hz, 1H), 4.11 (s,3H), 3.91 (d, J=16.8 Hz, 1H), 3.68 (dd, J=10.8, 13.7 Hz, 1H), 3.48-3.34(m), 3.19 (dd, J=4.15 Hz, 1H), 2.86-2.79 (m), 2.55-2.48 (m, 1H),2.11-2.08 (m), 1.89-1.74 (m). (ES MS M+1=549)

Step 3:[11-(3-Chloro-4-fluorobenzyl)-9-hydroxy-1,8,10-trioxo-1,3,4,5,6,8,10,11,12,13-deca-hydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridin-2-yl]aceticacid

A mixture of tert-butyl[11-(3-chloro-4-fluorobenzyl)-9-methoxy-1,8,10-trioxo-1,3,4,5,6,8,10,11,12,13-decahydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridin-2-yl]acetate(50 mg, 0.09 mmol) and 33% hydrogen bromide in acetic acid (1 mL) indioxane (1 mL) was stirred at room temperature for 1 hour. The productmixture was concentrated under vacuum. The residue was subjected toreverse phase column chromatography on C-18 stationary phase eluted witha 95-5% water-acetonitrile gradient. Collection and lyophilization ofappropriate fractions afforded the title compound.

¹H NMR (400 MHz, CDCl₃) δ 7.34 (dd, J=6.6, 2.1 Hz, 1H), 7.18 (br signal,1H), 7.11 (t, J=8.4 Hz, 1H), 4.78 (d, J=14.8 Hz, 1H), 4.52 (d, J=14.8Hz, 1H), 4.41 (d, J=17.8 Hz, 1H), 4.07 (d, J=17.8 Hz, 1H), 3.67 (m, 1H),3.51-3.36 (m), 3.23 (br d, 1H), 2.96 (m), 2.60 (m, 1H), 2.08 (m), 1.96(m), 1.76 (m). (ES MS M+1=478.2)

EXAMPLE 132-[11-(3-Chloro-4-fluorobenzyl)-9-hydroxy-1,8,10-trioxo-1,3,4,5,6,8,10,11,12,13-deca-hydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridin-2-yl]-N,N-dimethylacetamide

Step 1:2-[11-(3-Chloro-4-fluorobenzyl)-9-hydroxy-1,8,10-trioxo-1,3,4,5,6,8,10,11,12,13-deca-hydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridin-2-yl]-N,N-dimethylacetamide

A solution of[11-(3-chloro-4-fluorobenzyl)-9-hydroxy-1,8,10-trioxo-1,3,4,5,6,8,10,11,12,13-deca-hydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridin-2-yl]aceticacid (25 mg, 0.05 mmol), BOP (28 mg, 0.06 mmol), diisopropylethylamine(7 mg, 0.07 mmol) and dimethylamine (0.11 mL, 2M in THF) in DMF (0.5 mL)was stirred at room temperature overnight. The product mixture wasconcentrated under vacuum. The residue was subjected to reverse phasecolumn chromatography on C-18 stationary phase eluted with a 95-5%water-acetonitrile gradient. Collection and lyophilization ofappropriate fractions afforded the title compound.

¹H NMR (400 MHz, CDCl₃) δ 13.2 (br s, 1H), 7.35 (d, J=6.8 Hz, 1H), 7.18(br signal, 1H), 7.12 (t, J=8.4 Hz, 1H), 4.84 (m, 1H), 4.80 (d, J=14.8Hz, 1H), 4.66 (d, J=16.1 Hz, 1H), 4.52 (d, J=14.8 Hz, 1H), 3.89 (d,J=15.9 Hz, 1H), 3.68 (app t, J=12.2 Hz, 1H), 3.50-3.15 (br m, 4H), 3.07(s, 3H), 3.01-2.92 (br m, 4H), 2.77 (dt, J=5.3, 15.9 Hz, 1H), 2.14-2.08(m, 1H), 1.96-1.74 (br m, 3H). (ES MS M+1=505.3)

EXAMPLES 14-15

The compounds in the following table were prepared in accordance withthe procedure set forth in Example 13 using the appropriate amine inplace of dimethylamine.

Example Compound Data 14 2-[11-(3-Chloro-4-fluorobenzyl)-9- ES MS M + 1= 491.3 hydroxy-1,8,10-trioxo- 1,3,4,5,6,8,10,11,12,13-deca-hydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridin-2-yl]-N-methylacetamide

15 2-[11-(3-Chloro-4-fluorobenzyl)-9- HRMS (APCI, M + 1):hydroxy-1,8,10-trioxo- found 477.1334 1,3,4,5,6,8,10,11,12,13-deca-hydro-2H-[1,4]diazocino[2,1-a]- 2,6-naphthyridin-2-yl]acetamide

EXAMPLE 1611-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-(2-morpholin-4-ylethyl)-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

Step 1:11-(3-Chloro-4-fluorobenzyl)-9-methoxy-2-(2-hydroxyethyl)-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

A mixture of11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-[2-(benzyloxy)ethyl]-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione(0.55 g, 0.97 mmol) and 5% rhodium on carbon (1.10 g) in ethyl acetate(22 mL) was stirred under a balloon of hydrogen at room temperatureovernight. The product mixture was filtered through a pad of Celite. Thefiltrate was concentrated under vacuum to afford the title compound.This material was used in the following reaction without furtherpurification.

¹H NMR (400 MHz, CDCl₃) δ 7.37 (m, 1H), 7.22-7.19 (m, 1H), 7.10 (t,J=8.6 Hz, 1H), 4.83-4.61 (m, 3H), 4.19-4.00 (m, 4H), 3.93-3.80 (m, 2H),3.72-3.55 (m, 1H), 3.49-3.14 (br m, 5H), 2.96-2.81 (m, 1H), 2.48-2.34(m, 1H), 1.95-1.43 (br signal), 1.21-1.13 (br m, 1H), 0.93-0.84 (br m,1H). (ES MS M+1=478.1)

Step 2:11-(3-Chloro-4-fluorobenzyl)-9-methoxy-2-[2-(methanesulfonyloxy)ethyl]-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

To a cold (0° C.) solution of11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-(2-hydroxyethyl)-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione(250 mg, 0.52 mmol) and diisopropylethylamine (0.19 mL, 1.05 mmol) indichloromethane (5 mL), methanesulfonic anhydride (0.1 g, 0.63 mmol) wasadded. The reaction mixture was allowed to warm up to room temperatureand was stirred at room temperature for 2 hour. The product mixture wasdiluted with dichloromethane and washed with aq ammonium chloride. Theorganic extract was dried over anhydrous magnesium sulfate, filtered,and concentrated under vacuum to afford the title compound. Thismaterial was used in the following reaction without furtherpurification. (ES MS M+1=556.3)

Step 3:11-(3-Chloro-4-fluorobenzyl)-9-methoxy-2-(2-morpholin-4-ylethyl)-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

A mixture of11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-(2-methane-sulfonylethyl)-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione(97 mg, 0.17 mmol), morpholine (30 mg, 0.35 mmol), anddiisopropylethylamine (006 mL, 0.355 mmol) in THF (1.7 mL) was stirredat 40° C. overnight. The product mixture was concentrated under vacuum.The residue was subjected to column chromatography on silica gel elutingwith gradient mixture of methanol in dichloromethane. Collection andconcentration of appropriate fractions afforded the title compound.

¹H NMR (400 MHz, CDCl₃) δ 7.37 (dd, J=2.0, 7.0 Hz, 1H), 7.21 (m, 1H),7.12 (t, J=8.8 Hz, 1H), 4.80 (dd, J=6.2, 13.9 Hz, 1H), 4.74 (d, J=15.0Hz, 1H), 4.62 (d, J=14.8 Hz, 1H), 4.12-4.07 (m, 4H), 3.69-3.64 (m, 4H),3.45-3.30 (m, 5H), 3.20-3.13 (m, 1H), 2.90-2.83 (m, 1H), 2.66-2.42 (m,7H), 2.08 (br m, 1H), 1.91-1.72 (br m, 3H). (ES MS M+1=547.4)

Step 4:11-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-(2-morpholin-4-ylethyl)-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

A mixture of11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-(2-morpholin-4-ylethyl)-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione(30 mg, 0.06 mmol) and 33% hydrogen bromide in acetic acid (0.4 mL) indioxane (2 mL) was stirred at room temperature for 30 minutes. Theproduct mixture was concentrated under vacuum. The residue was subjectedto reverse phase column chromatography on C-18 stationary phase elutedwith a 95-5% water-acetonitrile gradient. Collection and lyophilizationof appropriate fractions afforded the title compound.

¹H NMR (400 MHz, CDCl₃) δ 13.3 (s, 1H), 7.35 (dd, J=2.0, 7.0 Hz, 1H),7.22-7.17 (m, 1H), 7.13 (t, J=8.7 Hz, 1H), 4.84-4.76 (m, 1H), 4.67 (appq, J=14.5 Hz, 2H), 4.43-4.36 (m, 1H), 4.02-2.85 (br signal, 17H),2.66-2.60 (m, 1H), 2.11-2.01 (br m, 1H), 1.94 (br m, 1H), 1.78-1.69 (brm, 2H). (ES MS M+1=533.3)

EXAMPLES 17-22

The compounds in the following table were prepared in accordance withthe procedure set forth in Example 16 using the appropriate amines orsodium alkoxide in place of morpholine in Examples 17-19 and 22.Acetylation and methanesulfonylation of the intermediate leading to thepreparation of 19 provided Examples 20 and 21.

Example Compound Data 17 11-(3-Chloro-4-fluorobenzyl)-9- ES MS M + 1 =517.3 hydroxy-2-(2-pyrrolidinyl-1- ylethyl)-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6- naphthyridine-1,8,10(11H)-trione

18 11-(3-Chloro-4-fluorobenzyl)-9- ES MS M + 1 = 531.2hydroxy-2-(2-piperidinyl-1- ylethyl)-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6- naphthyridine-1,8,10(11H)-trione

19 11-(3-Chloro-4-fluorobenzyl)-9- ES MS M + 1 = 463.2hydroxy-2-(2-aminoethyl)- 3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6- naphthyridine-1,8,10(11H)-trione

20 11-(3-Chloro-4-fluorohenzyl)-9- ES MS M + 1 = 505.3 hydroxy-2-[2-(acetylamino)ethyl]-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6- naphthyridine-1,8,10(11H)-trione

21 11-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-[2- ES MS M + 1 = 541.3(methanesulfonylamino)ethyl]- 3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine- 1,8,10(11H)-trione

22 11-(3-Ch1oro-4-flnorobenzyl)-9- ES MS M + 1 = 478.2hydroxy-2-[2-methoxy)ethyl]- 3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6- naphthyridine-1,8,10(11H)-trione

EXAMPLES 23-2411-(3-Chloro-4-fluorobenzyl)-4,9-dihydroxy-2-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

The title compound was prepared in a manner similar to that described inExample 10, steps 6 to 10, substitutingN-[2-(benzyloxy)ethyl]-4-{[tert-butyl(dimethyl)-silyl]oxy}butan-1-aminewith 4-{[tert-butyl(diphenyl)silyl]oxy}-1-(methylamino)butan-2-ol(Romeril, S. P. et al, Tet. Lett. 2003, 7757) in step 6.

Isomer A:

¹H NMR (600 MHz, CDCl₃) δ 13.09 (s, 1H), 7.35 (dd, J=1.6, 6.7 Hz, 1H),7.20-7.15 (m, 1H), 7.14-7.09 (m, 1H), 4.78 and 4.71 (d, J=14.2 Hz,second d overlaps with broad multiplet, 2H), 4.60 and 4.55 (d, J=14.9Hz, 1H), 4.16 and 3.96 (m, 1H), 3.77 and 3.62 (dd, J=10.8, 14.4 Hz, 1H),3.52-3.36 (m, 2H), 3.34-3.22 (m, 2H), 3.17 (s, 3H), 3.06-2.98 (m, 1H),2.67-2.48 (m, 2H), 1.94 (m).

Isomer B:

¹H NMR (600 MHz, CDCl₃) δ 13.13 (s, 1H), 7.35 (d, J=6.6 Hz, 1H), 7.18(m, 1H), 7.13 (t, J=8.5 Hz, 1H), 4.79 and 4.74 (d, J=15 Hz, 1H), 4.68(m, 1H), 4.59 and 4.54 (d, J=15 Hz, 1H), 4.16 and 3.96 (br signal, 1H),3.79 (m), 3.56-3.17 (m), 3.06-2.98 (m, 1H), 2.62-2.54 (m), 2.48 (br m),2.12 (br m), 1.90 (br m). (ES MS M+1=450.21)

EXAMPLE 2511-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-methyl-5,6,12,13-tetrahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,4,8,10(3H,11H)-tetrone

Step 1:11-(3-Chloro-4-fluorobenzyl)-4-hydroxy-9-methoxy-2-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

The title compound was prepared in a manner similar to that described inExample 10, steps 6 to 9, substitutingN-[2-(benzyloxy)ethyl]-4-{[tert-butyl(dimethyl)-silyl]oxy}butan-1-aminewith 4-{[tert-butyl(diphenyl)silyl]oxy}-1-(methylamino)butan-2-ol(Romeril, S. P. et al, Tet. Lett. 2003, 7757) in step 6.

Early Isomer on Normal Phase Silica (2:1 Mixture of Conformers):

¹H NMR (400 MHz, CDCl₃) δ 7.35 (d, J=6.8 Hz, 1H), 7.17 (m, 1H),7.10-7.07 (m, 1H), 4.89 and 4.71 (d, J=15 Hz, 1H), 4.67-4.63 (m, 1H),4.58 and 4.41 (d, J=15 Hz, 1H), 4.14 (br m), 4.08 and 3.96 (s, 3H), 3.90(m), 3.76-3.70 (m), 3.67-3.52 (m), 3.38 (br s), 3.42-3.21 (m), 3.16 (s),2.86-2.73 (m, 2H), 2.48-2.33 (m, 2H), 2.06 (m), 1.86-1.77 (m, 1H).

Late Isomer on Normal Phase Silica (5:2 Mixture of Conformers):

¹H NMR (400 MHz, CDCl₃) δ 7.36 (d, J=6.8 Hz, 1H), 7.17 (m, 1H),7.13-7.09 (m, 1H), 4.91 and 4.73 (d, J=14.7 Hz, 1H), 4.70-4.64 (m, 1H),4.61 and 4.44 (d, J=14.9 Hz, 1H), 4.17 (br s), 4.10 and 3.99 (s, 3H),3.92 (br m), 3.79-3.74 (m), 3.69-3.54 (m), 3.51 (br s), 3.42-3.24 (m),3.18 (s), 2.89-2.75 (m, 2H), 2.50-2.38 (m, 2H), 2.08 (br m), 1.88-1.73(m, 1H). (ES MS M+1=464.2)

Step 2:11-(3-Chloro-4-fluorobenzyl)-9-methoxy-2-methyl-5,6,12,13-tetrahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,4,8,10(3H,11H)-tetrone

A mixture of11-(3-chloro-4-fluorobenzyl)-4-hydroxy-9-methoxy-2-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione(50 mg, 0.11 mmol), molecular sieves (4A), N-methylmorpholine N-oxide(19 mg, 0.16 mmol), and tetra-n-propylammonium ruthenium tetroxide indichloromethane was stirred at room temperature for two hrs. The mixturewas filtered, and the filtrate concentrated under vacuum. The residuewas subjected to column chromatography on silica gel eluting with 0-15%methanol in dichloromethane gradient. Collection and concentration ofappropriate fractions provided the title compound.

¹H NMR (400 MHz, CDCl₃) δ 7.37 (d, J=6.2 Hz, 1H), 7.19 (m, 1H), 7.11 (t,J=8.5 Hz, 1H), 4.80 (d, J=14.1 Hz, 1H), 4.74 (d, J=15.2 Hz, 1H), 4.62(d, J=14.6 Hz, 1H), 4.15 (s, 3H), 4.10 (d, J=15.4 Hz, 1H), 3.66 (t,J=13.2 Hz, 1H), 3.52 (d, J=15.0 Hz, 1H), 3.45-3.36 (m, 2H), 3.11-3.04(m, 4H), 2.94-2.90 (m, 1H), 2.79 (d, J=18.9 Hz, 1H), 2.48-2.45 (m, 1H).(ES MS M+1=462.20)

Step 3:11-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-methyl-5,6,12,13-tetrahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,4,8,10(3H,11H)-tetrone

A mixture of11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-methyl-5,6,12,13-tetrahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,4,8,10(3H,11H)-tetrone(25 mg, 0.05 mmol) and 33% hydrogen bromide in acetic acid (0.5 mL) indioxane (1 mL) was stirred at room temperature for 1.5 hour. The productmixture was concentrated under vacuum. The residue was dissolved in DMSOand subjected to reverse phase column chromatography on C-18 stationaryphase eluted with a 95-5% water-acetonitrile gradient. Collection andlyophilization of appropriate fractions afforded the title compound.

¹H NMR (400 MHz, CDCl₃) δ 13.47 (s, 1H), 7.38 (d, J=6.0 Hz, 1H), 7.19(m, 1H), 7.12 (t, J=8.2 Hz, 1H), 5.56 (br s, 1H), 4.94 (br m, 1H), 4.23(br m, 2H), 4.16-3.98 (m, 2H), 3.60 (br d, J=8.1 Hz, 1H), 3.51 (br d,J=10.2 Hz, 1H), 3.24 (br signal, 1H), 2.89 (s, 3H), 2.59 (br signal,1H). (ES MS M+1=448.0)

EXAMPLE 2611-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-methyl-4-pyrrolidin-1-yl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

Step 1:11-(3-Chloro-4-fluorobenzyl)-4-pyrrolidin-1-yl-9-methoxy-2-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

A mixture of11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-methyl-5,6,12,13-tetrahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,4,8,10(3H,11H)-tetrone(30 mg, 0.06 mmol), molecular sieves (4A), pyrrolidine (23 mg, 0.32mmol), and acetic acid (4 mg) in dichloroethane (1 mL) was heated at 80°C. for four hrs. The mixture was cooled to room temperature, treatedwith sodium borohydride (12 mg, 0.19 mmol), and stirred at roomtemperature for 30 minutes. The product mixture was diluted withdichloromethane, washed successively with aq sodium carbonate and brine.The organic extract was dried over anhydrous magnesium sulfate,filtered, and concentrated under vacuum to provide the title compound.This material was used in the following step without furtherpurification.

ES MS M+1=517.3

Step 2:11-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-methyl-5,6,12,13-tetrahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,4,8,10(3H,11H)-tetrone

A mixture of11-(3-chloro-4-fluorobenzyl)-9-hydroxy-2-methyl-4-pyrrolidin-1-yl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione(40 mg, 0.08 mmol) and 33% hydrogen bromide in acetic acid (0.5 mL) indioxane (1 mL) was stirred at room temperature for 1.5 hour. The productmixture was concentrated under vacuum. The residue was dissolved in DMSOand subjected to reverse phase column chromatography on C-18 stationaryphase eluted with a 95-5% water-acetonitrile gradient. Collection andlyophilization of appropriate fractions afforded the title compound.

¹H NMR (400 MHz, CDCl₃) δ 7.36 (d, J=7.1 Hz, 1H), 7.17 (m, 1H), 7.13 (t,J=8.4 Hz, 1H), 4.84 (m, 1H), 4.70 (d, J=14.9 Hz, 1H), 4.63 (d, J=15.1Hz, 1H), 3.83 (m, 1H), 3.74 (m, 2H), 3.58 (dd, J=10 Hz, 1H), 3.48-3.43(m, 4H), 3.14 (s, 2H), 3.05-2.94 (br m, 2H), 2.63-2.58 (m, 1H), 2.40 (m,1H), 2.29-2.24 (m, 1H), 2.07 (br m, 3H). (ES MS M+1=503.2)

EXAMPLE 2711-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-methyl-4-morpholin-4-yl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

The title compound was prepared in a manner similar to that described inExample 26, substituting pyrrolidine with morpholine. ES MS M+1=518.99.

EXAMPLES 28-2911-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2,6-dimethyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

Step 1: 5-(Methylamino)pentan-2-ol

A mixture of γ-valerolactone (5.0 g, 49.9 mmol) and methylamine (75 mL,2 M in methanol) in methanol (50 mL) was stirred at room temperatureovernight. The product mixture was concentrated under vacuum. Thisintermediate methylamide was concentrated from benzene to removeresidual methanol and was used in the following step without furtherpurification. To a cold (0° C.) solution of the above amide (2.0 g, 15.3mmol) in anhydrous THF, a solution of lithium aluminum hydride (15.2 mL,2M) in THF was added. The reaction mixture was stirred at roomtemperature for 30 minutes, and heated at 65° C. overnight. The productmixture was cooled to 0° C. and treated successively with water (1.2mL), 15% aq sodium hydroxide (1.2 mL), and water (3.6 mL). The resultantsuspension was diluted with ether, and filtered with a pad of Celite.The solid filtered was washed with methylene chloride. The organicfiltrates were combined and concentrated under vacuum to provide thetitle compound.

Step 2:11-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2,6-dimethyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

The title compounds were prepared in a manner similar to that describedin Example 10, steps 5 to 10, substitutingN-[2-(benzyloxy)ethyl]-4-{[tert-butyl(dimethyl)-silyl]oxy}butan-1-aminewith 5-(methylamino)pentan-2-ol, and tert-butyldimethylsily chloridewith tert-butyldiphenylsily chloride in step 5. Two sets of enantiomericmixtures (atropisomeric at the exocyclic amide moiety and enantiomericat the 6-methyl position) were obtained with reverse phase HPLC on C-18stationary phase after hydrogen bromide deprotection in step 10.

Early Isomer on Reverse Phase:

¹H NMR (400 MHz, CDCl₃) δ 7.34 (d, J=6.3 Hz, 1H), 7.18 (br signal, 1H),7.13 (t, J=8.6 Hz, 1H), 4.78 (d, J=14.7 Hz, 1H), 4.55 (d, J=14.7 Hz,1H), 3.49-2.97 (m), 3.10 (s, 3H), 2.59-2.55 (m, 1H), 2.03 (br signal),1.74 (br signal), 1.36 (d, J=7.1 Hz, 3H). (ES MS exact massM+1=448.1466)

Late Isomer on Reverse Phase:

¹H NMR (400 MHz, CDCl₃) δ 7.34 (d, J=6.5 Hz, 1H), 7.18 (br signal, 1H),7.13 (t, J=8.6 Hz, 1H), 4.78 (d, J=14.7 Hz, 1H), 4.55 (d, J=14.7 Hz,1H), 4.05 (br t, J=6.6 Hz, 1H), 3.49-2.57 (m), 3.11 (s, 3H), 1.81 (brsignal), 1.72 (d, J=6.6 Hz, 3H). (ES MS exact mass M+1=448.1457)

EXAMPLES 30-36

The compounds in the following table were prepared in accordance withthe procedures set forth in Examples 11 and 29 using the appropriateaminoalcohol in place of 5-(methylamino)pentan-2-ol in Example 29. Theamino heterocycles were incorporated in the manner described in Examples16.

Example Compound 30 & 3111-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-(2-hydroxyethyl)-6-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

Early isomer on reverse phase: ¹H NMR (400 MHz, CDCl₃) δ 7.35 (dd, J =6.8, 1.8 Hz, 1H), 7.198 (br signal, 1H), 7.13 (t, J = 8.6 Hz, 1H), 5.72(m, 1H), 4.77 (d, J = 14.6 Hz, 1H), 4.54 (d, J = 14.6 Hz, 1H), 4.18 (m,1H), 3.92-3.78 (m, 2H), 3.50-2.92 (m), 2.55 (m, 1H), 2.01-1.75 (brsignals), 1.34 (d, J = 7.2 Hz, 3H). (ES MS exact mass M + 1 = 478.1548)Late isomer on reverse phase: ¹H NMR (400 MHz, CDCl₃) δ 7.35 (dd, J =6.8, 1.6 Hz, 1H), 7.19 (br signal, 1H), 7.12 (t, J = 8.6 Hz, 1H), 4.78(d, J = 14.6 Hz, 1H), 4.54 (d, J = 14.6 Hz, 1H), 4.18- 4.06 (m, 2H),4.04-3.78 (m, 2H), 3.51-3.00 (m), 2.78-2.56 (m), 1.83-1.77 (br signals),1.71 (d, J = 6.7 Hz, 3H).. (ES MS exact mass M + 1 = 478.1551) 3211-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-(2-morpholin-4-ylethyl)-6-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

(ES MS M + 1 = 547.2) 3311-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-(2-piperidinyl-1-ylethyl)-6-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

(ES MS M + 1 = 545.2) 3411-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-(2-pyrrolidinyl-1-ylethyl)-6-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

(ES MS M + 1 = 531.2) 3511-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-[2-(1H-pyrazol-1-yl)ethyl]-6-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

(ES MS M + 1 = 528.2) 3611-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2-[2-(1H-imidazol-1-yl)ethyl]-6-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

(ES MS M + 1 = 528.2)

EXAMPLE 3711-(3-Chloro-4-fluorobenzyl)-5,9-dihydroxy-2-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

The title compound was prepared in a manner similar to that described inExample 10, steps 6 to 10, substitutingN-[2-(benzyloxy)ethyl]-4-{[tert-butyl(dimethyl)-silyl]oxy}butan-1-aminewith N-methyl-3-benzyloxy-4-hydroxybutan-1-amine in step 6.

¹H NMR (400 MHz, CDCl₃) δ 7.34 (d, J=6.8 Hz, 1H), 7.18 (m, 1H), 7.12 (t,J=8.4 Hz, 1H), 5.30 (s), 4.78 (d, J=14.7 Hz, 1H), 4.71 (br d, 1H), 4.54(d, J=14.7 Hz, 1H), 4.08 (br signal, 1H), 3.54-3.34 (m) 3.20-2.98 (m),3.13 (s, 3H). (ES MS M+1=450.2)

EXAMPLE 38(4R/S)-11-(3-Chloro-4-fluorobenzyl)-4,9-dihydroxy-2,5,5-trimethyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

Step 1: (3R)-3-(Benzyloxy)-4,4-dimethyldihydrofuran-2(3H)-one

A mixture of D(−)-pantolactone (20.0 g, 153.7 mmol) and sodium hydride(4.4 g, 184.4 mmol) in anhydrous THF was stirred under an atmosphere ofnitrogen at room temperature for 1 hour. The resultant mixture wastreated with benzyl bromide (31.5 g, 184.4 mmol) and stirred at roomtemperature overnight. The product mixture was treated with water anddiluted with dichloromethane. The organic extract was washed with brine,dried over anhydrous magnesium sulfate, filtered, and concentrated undervacuum. The residue was subjected to purification on silica gel elutingwith 0-5% methanol in dichloromethane gradient. Collection andconcentration of appropriate fractions provided the title compound.

¹H NMR (400 MHz, CDCl₃) δ 7.39-7.29 (m, 5H), 5.03 (d, J=12.1 Hz, 1H),4.75 (d, J=12.1 Hz, 1H), 4.00 (d, J=8.8 Hz, 1H), 3.86 (d, J=8.8 Hz, 1H),3.74 (s, 1H), 1.14 (s, 3H), 1.10 (s, 3H).

Step 2: (3R)-3-(Benzyloxy)-2,2-dimethyl-4-(methylamino)butan-1-ol

The title compounds were prepared in a manner similar to that describedin Examples 28-29, step 1, substituting γ-valerolactone with(3R)-3-(benzyloxy)-4,4-dimethyldihydrofuran-2(3H)-one.

¹H NMR (400 MHz, CDCl₃) δ 7.41-7.32 (m, 5H), 6.63 (br s, 1H), 4.55 (d,J=11.4 Hz, 1H), 4.47 (d, J=11.4 Hz, 1H), 3.79 (s, 1H), 3.48 (s, 1H),3.43 (d, J=11.8 Hz, 1H), 3.37 (d, J=11.8 Hz, 1H), 2.84 (d, J=5.0 Hz,3H), 1.06 (s, 3H), 0.85 (s, 3H).

Step 3:(4R/S)-11-(3-Chloro-4-fluorobenzyl)-4,9-dihydroxy-2,5,5-trimethyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

The title compound was prepared in a manner similar to that described inExample 10, steps 6, 8 to 10, substitutingN-[2-(benzyloxy)ethyl]-4-{[tert-butyl(dimethyl)-silyl]oxy}butan-1-aminewith (3R)-3-(benzyloxy)-2,2-dimethyl-4-(methylamino)butan-1-ol in step6.

¹H NMR (400 MHz, CDCl₃) δ 7.4 (dd, J=1.6, 5.4 Hz, 1H), 7.2 (m, 1H), 7.13(t, J=8.4 Hz, 1H), 4.84 (d, J=14.6 Hz, 1H), 4.75 (d, J=14.8 Hz, 1H),4.58 (d, J=14.8 Hz, 1H), 3.71 (dd, J=15.0, 9.7 Hz, 1H), 3.44 (m), 3.19(s, 3H), 3.19 (m), 3.03 (d, J=15.0 Hz, 1H), 2.94 (m, 1H), 2.54 (m, 1H),1.22 (s, 3H), 0.93 (s, 3H). (ES MS M+1=478.2)

EXAMPLES 39-44

The compounds in the following table were prepared in accordance withthe procedure set forth in Example 38 using the appropriate lactone inplace of D(−)-pantolactone.

Example Compound Data 39(4S)-11-(3-Chloro-4-fluorobenzyl)-4,9-dihydroxy-2,5,5- (ES MS M + 1 =478.2) trimethyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

L-(−)-pantolactone 40 & 41(4R/S)-11-(3-Chloro-4-fluorobenzyl)-4,9-dihydroxy-2,5,5- (ES MS M + 1 =478.2) trimethyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

(racemic D/L pantoyl lactone 42(4R/S)-11-(4-Fluorobenzyl)-4,9-dihydroxy-2,5,5-trimethyl- (ES MS M + 1 =448.2) 3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

43 (4R, 6S)-11-(3-Chloro-4-fluorobenzyl)-4,9-dihydroxy-2,6- (ES MS M + 1= 464.1) dimethyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

44 (4S, 6S)-11-(3-Chloro-4-fluorobenzyl)-4,9-dihydroxy-2,6- (ES MS M + 1= 464.1) dimethyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

EXAMPLE 4511-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2,4,4-trimethyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

The title compound was prepared in a manner similar to that described inExample 10, steps 6 to 10, substitutingN-[2-(benzyloxy)ethyl]-4-{[tert-butyl(dimethyl)-silyl]oxy}butan-1-aminewith 4-{[tert-butyl(diphenyl)-silyl]oxy}-N,2,2-trimethylbutan-1-amine instep 6.

¹H NMR (400 MHz, CDCl₃) δ 7.35 (dd, J=1.6, 6.8 Hz, 1H), 7.2 (m, 1H),7.13 (t, J=8.6 Hz, 1H), 4.79 (d, J=14.9 Hz, 1H), 4.70 (m, 4H), 4.54 (d,J=14.9 Hz, 1H), 3.53 (m), 3.18 (s, 3H), 3.05-2.93 (m), 2.84 (d, J=15.2Hz, 1H), 2.56-2.48 (m), 1.85-1.66 (m), 1.12 (s, 3H), 0.89 (s, 3H). (ESMS exact mass M+1=462.1600)

EXAMPLE 4611-(3-Chloro-4-fluorobenzyl)-9-hydroxy-2,4-dimethyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

The title compounds were prepared in a manner similar to that describedin Examples 28-29, substituting γ-valerolactone withα-methyl-γ-butyrolactone.

¹H NMR (400 MHz, CDCl₃) δ 7.36-7.30 (m, 1H), 7.21-7.18 (br signal, 1H),7.13 (t, J=8.6 Hz, 1H), 4.80 (d, J=14.6 Hz, 1H), 4.80 (m), 4.53 (d,J=14.6 Hz, 1H), 3.50-2.53 (m), 3.11 (s, 3H), 2.18-1.53 (m), 0.90 (d,J=7.0 Hz, 3H). (ES-MS M+1=448.17)

EXAMPLE 47(6R)-11-(3-Chloro-4-fluorobenzyl)-9-hydroxy-6-(hydroxymethyl)-2-methyl-3,4,5,6,12,13-hexahydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

Step 1: (2S)-1-(Benzyloxy)-5-(methylamino)pentan-2-ol

The title compound was prepared in a manner similar to that described inExamples 28-29, step 1, substituting γ-valerolactone with(5S)-5-[(benzyloxy)methyl]dihydrofuran-2(3H)-one. (ES MS M+1=224.0).

Step 2:6-(3-Chloro-4-fluorobenzyl)-N-[(4S)-4,5-dihydroxypentyl]-4-methoxy-N-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide

The title compound was prepared in a manner similar to that described inExample 10, step 6, substitutingN-[2-(benzyloxy)-ethyl]-4-{[tert-butyl(dimethyl)silyl]oxy}butan-1-aminewith (2S)-1-(benzyloxy)-5-(methylamino)pentan-2-ol. (ES MS M+1=586.33)

Step 3:(6R)-6-[(Benzyloxy)methyl]-11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

The title compound was prepared in a manner similar to that described inExample 10, steps 8 and 9, substitutingN-[2-(benzyloxy)ethyl]-N-(4-hydroxybutyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamidewith6-(3-chloro-4-fluorobenzyl)-N-[(4S)-4,5-dihydroxypentyl]-4-methoxy-N-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamidein step 8. (ES MS M+1=568.3)

Step 4:(6R)-11-(3-Chloro-4-fluorobenzyl)-9-hydroxy-6-(hydroxymethyl)-2-methyl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

A solution of(6R)-6-[(benzyloxy)methyl]-11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-methyl-3,4,5,6,12,13-hexahydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione(167 mg, 0.29 mmol) in dichloromethane (2.9 mL) was cooled to 0° C. andtreated with boron tribromide (295 mg, 1.18 mmol). The cooling bath wasremoved and the mixture stirred at room temperature for 30 minutes. Thereaction was quenched by the addition of MeOH followed by 1 N aqueousHCl. The mixture was diluted with dichloromethane and washed with water.The organic layer was dried over anhydrous magnesium sulfate, filteredand concentrated under vacuum. The residue was subjected to reversephase column chromatography on C-18 stationary phase eluted with a 95-5%water-acetonitrile gradient. Collection and concentration of appropriatefractions afforded the title compound.

¹H NMR (400 MHz, CDCl₃) δ 13.15 (br s, 1H), 7.35 (d, J=6.8 Hz, 1H), 7.19(m, 1H), 7.13 (t, J=8.5 Hz, 1H), 4.80 (d, J=14.6 Hz, 1H), 4.54 (d,J=14.6 Hz, 1H), 4.40-4.10 (br signal), 4.04-3.92 (m, 3H), 3.8-3.6 (brm), 3.54-3.47 (m), 3.41-3.31 (m), 3.22-3.16 (m), 3.10 (s, 3H), 3.06-2.99(m, 1H), 2.61-2.54 (m, 1H), 2.25-2.15 (m, 2H), 1.85-1.80 (m, 2H),1.26-1.14 (m). (ES MS M+1=464.3)

EXAMPLE 48(6R)-11-(4-Fluorobenzyl)-9-hydroxy-6-(hydroxymethyl)-2-methyl-3,4,5,6,12,13-hexahydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

A mixture of(6R)-11-(3-chloro-4-fluorobenzyl)-9-hydroxy-6-(hydroxymethyl)-2-methyl-3,4,5,6,12,13-hexahydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione(109 mg, 0.24 mmol), 20% Pd(OH)₂ on carbon (40 mg) anddiisopropylethylamine (0.1 mL) in EtOH (2.4 mL) was stirred underhydrogen atmosphere for 20 hours. The reaction mixture was filteredthrough a Celite pad and the filtrate concentrated under vacuum toafford the title compound.

¹H NMR (400 MHz, CDCl₃) δ 7.30-7.28 (m), 7.04 (t, J=8.5 Hz, 2H), 4.80(d, J=14.6 Hz, 1H), 4.59 (d, J=14.6 Hz, 1H), 4.06-4.04 (m, 2H),3.95-3.92 (m, 1H), 3.53-3.45 (m, 1H), 3.40-3.28 (m, 2H), 3.22-3.17 (m,1H), 3.04-2.97 (m, 1H), 2.59-2.52 (m, 1H), 2.23-2.21 (m, 2H), 1.81 (m,2H). (ES MS M+1=430.2)

EXAMPLE 49(6S)-11-(3-Chloro-4-fluorobenzyl)-9-hydroxy-6-(hydroxymethyl)-2-methyl-3,4,5,6,12,13-hexahydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

The title compound was prepared in a manner similar to that described inExample 46 and was isolated as a mixture of atropisomers. Furtherpurification by reverse phase column chromatography on a C18 column(gradient elution with 70% H₂O—CH₃CN to 65% H₂O—CH₃CN over 30 minutes,then isocratic elution with 65% H₂O—CH₃CN for 10 minutes) afforded thetitle compound as the less polar atropisomer.

¹H NMR (400 MHz, CDCl₃) δ 13.11 (s, 1H), 7.36-7.34 (m, 1H), 7.21-7.10(m, 2H), 4.78 (d, J=14.7 Hz, 1H), 4.55 (d, J=14.7 Hz, 1H), 4.01-3.90 (m,3H), 3.54-3.42 (m, 1H), 3.40-3.30 (m, 2H), 3.21-3.17 (m, 1H), 3.09 (s,3H), 3.06-3.00 (m, 1H), 2.60-2.53 (m, 1H), 2.23-2.15 (m, 2H), 1.84-1.80(m, 2H). HRMS (ES M+1): found 464.1400; calculated 464.1383.

The more polar isomer was also isolated from the mixture:

¹H NMR (400 MHz, CDCl₃) δ 13.09 (s, 1H), 7.36 (dd, J=1.9, 6.8 Hz, 1H),7.22-7.10 (m, 2H), 5.68 (br s, 1H), 4.82 (d, J=14.8 Hz, 1H), 4.52 (d,J=14.8 Hz, 1H), 3.72-3.66 (m, 2H), 3.53-3.46 (m, 1H), 3.38-3.32 (m, 2H),3.16-2.82 (m, 5H), 2.53-2.45 (m, 1H), 2.05-2.01 (m, 2H), 1.78-1.69 (m,2H). HRMS (ES M+1): found 464.1402; calculated 464.1383.

EXAMPLE 5011-(3-chloro-4-fluorobenzyl)-9-hydroxy-2-methyl-6-methylene-3,4,5,6,12,13-hexahydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione

The title compound was generated during the boron tribromide-mediateddeprotection of(6S)-6-[(benzyloxy)methyl]-11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-methyl-3,4,5,6,12,13-hexahydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trionefollowing the method described in Example 47, step 4 for deprotection ofthe corresponding (6R)-isomer, and was isolated by reverse phase columnchromatography on C-18 stationary phase eluted with a 95-5%water-acetonitrile gradient. HRMS (ES M+1): found 446.1264; calculated446.1277.

EXAMPLE 512-[8-(3-Chloro-4-fluorobenzyl)-6-hydroxy-3,3-dimethyl-2,5,7-trioxo-2,3,7,8,9,10-hexahydroimidazo[2,1-a]-2,6-naphthyridin-1(5H)-yl]-N,N-dimethylacetamide

Step 1: tert-Butyl[8-(3-Chloro-4-fluorobenzyl)-6-methoxy-3,3-dimethyl-2,5,7-trioxo-2,3,7,8,9,10-hexahydroimidazo[2,1-a]-2,6-naphthyridin-1(5H)-yl]acetate

A mixture of8-(3-chloro-4-fluorobenzyl)-6-methoxy-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine-2,5,6(3H)-trione(1.00 g, 2.55 mmol; Example 8, step 5), sodium hydride (112 mg, 60%dispersion; 2.81 mmol), tert-butyl bromoacetate (0.55 g, 2.81 mmol) inanhydrous DMF (10 mL) was stirred at room temperature overnight. Thereaction mixture was concentrated under vacuum. The residue was subjectto column chromatography on silica gel. Collection and concentration ofappropriate fractions provided the required alkylated intermediate. Amixture of the above material (0.49 g, 0.99 mmol), sodium hydride (71mg, 60% dispersion; 2.96 mmol), iodomethane (0.42 g, 2.96 mmol) inanhydrous DMF (10 mL) was stirred at room temperature overnight. Thereaction mixture was concentrated under vacuum. The residue was subjectto column chromatography on silica gel. Collection and concentration ofappropriate fractions afforded the title compound. ES MS M+1=534.2

Step 2:2-[8-(3-Chloro-4-fluorobenzyl)-6-hydroxy-3,3-dimethyl-2,5,7-trioxo-2,3,7,8,9,10-hexahydroimidazo[2,1-a]-2,6-naphthyridin-1(5H)-yl]-N,N-dimethylacetamide

A mixture of tert-butyl[8-(3-Chloro-4-fluorobenzyl)-6-methoxy-3,3-dimethyl-2,5,7-trioxo-2,3,7,8,9,10-hexahydroimidazo[2,1-a]-2,6-naphthyridin-1(5H)-yl]acetate(0.30 g, 0.56 mmol) and hydrogen chloride (2.8 mL, 4 M in dioxane) indioxane (5 mL) was stirred at room temperature overnight. The reactionmixture was concentrated under vacuum. The residue was triturated withdiethyl ether and filtered to provide the title compound. Thisintermediate acid was used in the following step without furtherpurification. A solution of the acid (40 mg, 0.08 mmol), BOP (48 mg,0.11 mmol), diisopropylethylamine (12 mg, 0.12 mmol) and dimethylamine(0.04 mL, 2M in THF) in DMF (0.5 mL) was stirred at room temperatureovernight. The product mixture was concentrated under vacuum. Theresidue was subjected to column chromatography on silica gel. Collectionand concentration of appropriate fractions afforded the penultimateproduct. This material (28 mg, 0.06 mmol) was treated with 33% hydrogenbromide in acetic acid (44 mg) in dioxane (1 mL) at room temperature for1.5 hour. The product mixture was concentrated under vacuum. The residuewas dissolved in DMSO and subjected to reverse phase columnchromatography on C-18 stationary phase eluted with a 95-5%water-acetonitrile gradient. Collection and lyophilization ofappropriate fractions afforded the title compound.

¹H NMR (400 MHz, CDCl₃) δ 7.33 (br d, J=6.8 Hz, 1H), 7.18 (br signal,1H), 7.13 (t, J=8.4 Hz, 1H), 4.65 (s, 3H), 4.63 (s, 3H), 3.40 (brsignal, 2H), 3.08 (s, 3H), 2.98 (s, 3H), 2.73 (br signal, 2H), 1.84 (s,6H) (ES MS exact mass M+1=491.1570)

EXAMPLES 52-53

The compounds in the following table were prepared in accordance withthe procedure set forth in Example 51 using the appropriate amine inplace of dimethylamine.

Example Compound Data 522-[8-(3-Chloro-4-fluorobenzyl)-6-hydroxy-3,3-dimethyl-2,5,7- (ES MSexact mass trioxo-2,3,7,8,9,10-hexahydroimidazo[2,1-a]-2,6-naphthyridin-M + 1 = 477.1343) 1(5H)-yl]-N-methylacetamide

53 2-[8-(3-Chloro-4-fluorobenzyl)-6-hydroxy-3,3-dimethyl-2,5,7- (ES MSexact mass trioxo-2,3,7,8,9,10-hexahydroimidazo[2,1-a]-2,6-naphthyridin-M + 1 = 463.1179) 1(5H)-yl]acetamide

EXAMPLE 548-(3-Chloro-4-fluorobenzyl)-6-hydroxy-1-(2-hydroxyethyl)-3,3-dimethyl-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine-2,5,7(3H)-trione

The title compound was prepared in a manner similar to that described inExample 50, substituting tert-butyl bromoacetate with2-benzyloxyethylbromide in step 1.

¹H NMR (400 MHz, CDCl₃) δ 7.36 (dd, J=6.8, 1.8 Hz, 1H), 7.20 (br signal,1H), 7.13 (t, J=8.6 Hz, 1H), 5.30 (s, 1H), 4.68 (s, 2H), 4.02 (t, J=5.5Hz, 2H), 3.87 (t, J=5.5 Hz, 2H), 3.44 (t, J=6.2 Hz, 2H), 3.04 (t, J=6.2Hz, 2H), 1.79 (s, 6H) (ES MS exact mass M+1=450.1225)

EXAMPLES 55-56

The compounds in the following table were prepared in accordance withthe procedure set forth in Example 55 using the appropriatebenzyloxyalkyl bromide in place of 2-benzyloxyethylbromide.

Example Compound Data 558-(3-Chloro-4-fluorobenzyl)-6-hydroxy-1-(3-hydroxypropyl)-3,3- (ES MSexact mass dimethyl-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine-M + 1 = 464.1408) 2,5,7(3H)-trione

56 8-(3-Chloro-4-fluorobenzyl)-6-hydroxy-1-(4-hydroxybutyl)-3,3- (ES MSexact mass dimethyl-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine-M + 1 = 478.1548) 2,5,7(3H)-trione

EXAMPLE 578-(3-Chloro-4-fluorobenzyl)-6-hydroxy-1-(2-acetyloxyethyl)-3,3-dimethyl-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine-2,5,7(3H)-trione

The title compound was prepared in a manner similar to that described inExample 54, except 33% hydrogen bromide in acetic acid was used in thefinal demethylation step.

¹H NMR (400 MHz, CDCl₃) δ 7.35 (br d, J=6.8 Hz, 1H), 7.20 (br signal,1H), 7.14 (t, J=8.4 Hz, 1H), 4.68 (s, 2H), 4.27 (t, J=5.5 Hz, 2H), 4.12(t, J=5.5 Hz, 2H), 3.49 (t, J=6.2 Hz, 2H), 3.02 (t, J=6.2 Hz, 2H), 2.02(s, 3H), 1.80 (s, 6H) (ES MS exact mass M+1=492.1342)

EXAMPLES 58-60

The compounds in the following table were prepared in accordance withthe procedure set forth in Example 57 using the appropriatebenzyloxyalkyl bromide in place of 2-benzyloxyethylbromide.

Example Compound Data 588-(3-Chloro-4-fluorobenzyl)-6-hydroxy-1-(3-acetyloxypropyl)- (ES MSexact mass 3,3-dimethyl-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6- M + 1 =506.1480) naphthyridine-2,5,7(3H)-trione

59 8-(3-Chloro-4-fluorobenzyl)-6-hydroxy-1-(4-acetyloxybutyl)-3,3- (ESMS exact massdimethyl-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine- M + 1 =520.1645) 2,5,7(3H)-trione

60 8-(3-Chloro-4-fluorohenzyl)-6-hydroxy-1,3-bis(2-hydroxyethyl)- (ES MSexact mass 3-methyl-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine-M + 1 = 480.1350) 2,5,7(3H)-trione

EXAMPLE 6111-(3-Chloro-4-fluorobenzyl)-9-hydroxy-3,4,5,6,12,13-hexahydro-[1,4]oxazocino[3,4-a]-2,6-naphthyridine-1,8,10(11H)-trione

A mixture of6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide(0.80 g, 2.19 mmol; Example 1, step 9) and magnesium methoxide inmethanol (10.6 mL, 6-10% methanol solution available from Aldrich) inDMSO (22 mL) was heated at 60° C. for 30 minutes. Methanol wasexhaustively removed under vacuum over 45 minutes. The residual DMSOsolution was treated with 1-bromo-4-chlorobutane (1.80 g, 10.50 mmol)and stirred at 60° C. under an atmosphere of nitrogen overnight. Thereaction mixture was heated at 100° C. for 3 hrs. The reaction mixturewas treated with dilute HCl. The solid precipitated was filtered,dissolved in DMSO, and subjected to reverse phase HPLC purification.Collection and lyophilzation of appropriate fractions provided the titlecompound.

¹H NMR (400 MHz, CDCl₃) δ 13.4 (br s, 1H), 7.38 (dd, J=1.6, 6.6 Hz, 1H),7.20 (m, 1H), 7.14 (t, J=8.6 Hz, 1H), 4.68 (s, 2H), 4.26 (br signal,2H), 3.46 (t, J=6.4 Hz, 2H), 2.83 (br signal, 2H), 2.00 (br signal, 4H).(ES MS exact mass M+1=421.0966)

EXAMPLE 6210-(3-Chloro-4-fluorobenzyl)-8-hydroxy-4,5,11,12-tetrahydro-3H-[1,4]oxazepino[3,4-a]-2,6-naphthyridine-1,7,9(10H)-trione

The title compound was prepared in a manner similar to that described inExample 61, substituting 1-bromo-4-chlorobutane with1-bromo-3-chloropropane.

¹H NMR (400 MHz, CDCl₃) δ 13.78 (s, 1H), 7.38 (dd, J=2, 7 Hz, 1H), 7.18(m, 1H), 7.14 (t, J=8.6 Hz, 1H), 4.68 (s, 2H), 4.23 (t, J=6 Hz, 2H),3.45 (t, J=6 Hz, 2H), 2.97 (t, J=6 Hz, 2H), 2.23 (t, J=6 Hz, 2H). (ES MSexact mass M+1=407.0819)

EXAMPLE 639-(3-Chloro-4-fluorobenzyl)-7-hydroxy-3-(acetyloxymethyl)-3,4,10,11-tetrahydro[1,4]oxazino[3,4-a]-2,6-naphthyridine-1,6,8(9H)-trione

Step 1: Methyl2-(allyl)-6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate

A mixture of6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide(3.99 g, 10.51 mmol; Example 1, step 9) and magnesium methoxide inmethanol (52.4 mL, 6-10% methanol solution available from Aldrich) inDMSO (100 mL) was heated at 60° C. for 30 minutes. Methanol wasexhaustively removed under vacuum over 45 minutes. The residual DMSOsolution was treated with allyl bromide (3.810 g, 31.52 mmol) andstirred at room temperature under an atmosphere of nitrogen forovernight. The reaction mixture was treated dilute hydrochloric acid.The solid precipitated was filtered to provide the title compound. (ESMS M+1=421.2)

Step 2: Methyl2-(allyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate

A mixture of methyl2-(allyl)-6-(3-chloro-4-fluorobenzyl)-4-hydroxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate(6.08 g, 14.92 mmol), cesium carbonate (6.08 g, 18.65 mmol), andiodomethane (2.79 mL, 44.77 mmol) in DMF (20 mL) was heated at 40° C.overnight. The reaction mixture was filtered and concentrated undervacuum. The residue was subjected to column chromatography on silicagel. Collection and concentration of appropriate fractions provided thetitle compound. (ES MS M+1=435.2)

Step 3:9-(3-Chloro-4-fluorobenzyl)-3-(hydroxymethyl)-7-methoxy-3,4,10,11-tetrahydro[1,4]oxazino[3,4-a]-2,6-naphthyridine-1,6,8(9H)-trione

A mixture of methyl2-(allyl)-6-(3-chloro-4-fluorobenzyl)-4-methoxy-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate(0.20 g, 0.46 mmol), N-methylmorpholine N-oxide (67 mg, 0.58 mmol),water (0.2 mL), and osmium tetroxide (0.75 mL, 0.08 M in t-butanol) inacetone (1 mL) was stirred at room temperature overnight. The productmixture was concentrated under vacuum. The residue was subjected tocolumn chromatography on silica gel. Collection and concentration ofappropriate fractions provided the title compound. (ES MS M+1=437.2)

Step 4:9-(3-Chloro-4-fluorobenzyl)-7-hydroxy-3-(acetyloxymethyl)-3,4,10,11-tetrahydro[1,4]oxazino[3,4-a]-2,6-naphthyridine-1,6,8(9H)-trione

A mixture of9-(3-chloro-4-fluorobenzyl)-3-(hydroxymethyl)-7-methoxy-3,4,10,11-tetrahydro[1,4]oxazino[3,4-a]-2,6-naphthyridine-1,6,8(9H)-trione(50 mg, 0.11 mmol) and 33% hydrogen bromide in acetic acid (0.1 g) inacetic acid (1 mL) was stirred at room temperature for 30 minutes. Theproduct mixture was concentrated under vacuum. The residue was dissolvedin DMSO and subjected to reverse phase column chromatography on C-18stationary phase eluted with a 95-5% water-acetonitrile gradient.Collection and lyophilization of appropriate fractions afforded thetitle compound.

¹H NMR (400 MHz, CDCl₃) δ 7.60 (1H), 7.42 (1H), 7.38 (1H), 4.86 (1H),4.71 (2H), 4.68 (1H), 4.34 (2H), 3.82 (1H), 3.50 (2H), 3.20 (2H), 2.07(3H). (ES MS exact mass M+1=465.0851)

EXAMPLE 649-(3-Chloro-4-fluorobenzyl)-7-hydroxy-3-(hydroxymethyl)-3,4,10,11-tetrahydro[1,4]oxazino[3,4-a]-2,6-naphthyridine-1,6,8(9H)-trione

A mixture of9-(3-chloro-4-fluorobenzyl)-7-hydroxy-3-(acetyloxymethyl)-3,4,10,11-tetrahydro[1,4]oxazino[3,4-a]-2,6-naphthyridine-1,6,8(9H)-trione(46 mg, 0.10 mmol) and 30% sodium methoxide in methanol (39 mg) indioxane (1.5 mL) was stirred at room temperature for 2 hours. Theproduct mixture was concentrated under vacuum. The residue was dissolvedin DMSO and subjected to reverse phase column chromatography on C-18stationary phase eluted with a 95-5% water-acetonitrile gradient.Collection and lyophilization of appropriate fractions afforded thetitle compound.

¹H NMR (400 MHz, CDCl₃) δ 7.37 (dd, J=6.8, 1.8 Hz, 1H), 7.21 (br signal,1H), 7.15 (t, J=8.6 Hz, 1H), 4.89 (d, J=14.6 Hz, 1H), 4.69 (s, 2H),4.03-3.82 (m, 4H), 3.47-3.30 (m, 5H), 2.29 (br s, 3H). (ES MS exact massM+1=423.0754)

EXAMPLE 65

Oral Compositions

As a specific embodiment of an oral composition of a compound of thisinvention, 50 mg of compound of Example 1 is formulated with sufficientfinely divided lactose to provide a total amount of 580 to 590 mg tofill a size 0 hard gelatin capsule. Encapsulated oral compositionscontaining any one of the compounds of Examples 2 to 64 can be similarlyprepared.

EXAMPLE 66

HIV Integrase Assay: Strand Transfer Catalyzed by Recombinant Integrase

Assays for the strand transfer activity of integrase were conducted inaccordance with WO 02/30930 for recombinant integrase. Representativecompounds of the present invention exhibit inhibition of strand transferactivity in this assay. For example, the compounds of Examples 1 to 64were tested in the integrase assay and found to have IC₅₀ values of lessthan about 1 micromolar.

Further description on conducting the assay using preassembled complexesis found in Wolfe, A. L. et al., J. Virol. 1996, 70: 1424-1432, Hazudaet al., J. Virol. 1997, 71: 7005-7011; Hazuda et al., Drug Design andDiscovery 1997, 15: 17-24; and Hazuda et al., Science 2000, 287:646-650.

EXAMPLE 67

Assay for Inhibition of HIV Replication

Assays for the inhibition of acute HIV infection of T-lymphoid cellswere conducted in accordance with Vacca, J. P. et al., Proc. Natl. Acad.Sci. USA 1994, 91: 4096. Representative compounds of the presentinvention exhibit inhibition of HIV replication in this assay (alsoreferred to herein as the “spread assay”). For example, the compounds ofExamples 1 to 64 were tested in this assay and found to have IC₉₅ valuesof less than about 10 micromolar.

EXAMPLE 68

Cytotoxicity

Cytotoxicity was determined by microscopic examination of the cells ineach well in the spread assay, wherein a trained analyst observed eachculture for any of the following morphological changes as compared tothe control cultures: pH imbalance, cell abnormality, cytostatic,cytopathic, or crystallization (i.e., the compound is not soluble orforms crystals in the well). The toxicity value assigned to a givencompound is the lowest concentration of the compound at which one of theabove changes is observed. Representative compounds of the presentinvention that were tested in the spread assay (see Example 67) wereexamined for cytotoxicity up to a concentration of 10 micromolar, and nocytotoxicity was exhibited. In particular, the compounds set forth inExamples 1 to 64 exhibited no cytotoxicity at concentrations up to 10micromolar.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, thepractice of the invention encompasses all of the usual variations,adaptations and/or modifications that come within the scope of thefollowing claims.

1. A compound of Formula I, or a pharmaceutically acceptable saltthereof:

wherein: bond

in the ring is a single bond or a double bond; R¹ is C₁₋₆ alkyl, R^(J),or C₁₋₆ alkyl substituted with R^(J), wherein R^(J) is CycA, AryA, HetA,or HetP; R² is H or C₁₋₆ alkyl; R³ is: (1) H, (2) halogen, (3) CN, (4)C₁₋₆ alkyl, (5) C₁₋₆ haloalkyl, (6) C₁₋₆ alkyl substituted with OH,O—C₁₋₆ alkyl, O—C₁₋₆ haloalkyl, CN, N(R^(A))R^(B), C(O)N(R^(A))R^(B),C(O)R^(A), CO₂R^(A), C(O)—N(R^(A))—C₁₋₆ alkylene-OR^(B) with the provisothat the N(R^(A)) moiety and the OR^(B) moiety are not both attached tothe same carbon of the C₁₋₆ alkylene moiety, SR^(A), S(O)R^(A),SO₂R^(A), SO₂N(R^(A))R^(B), N(R^(A))C(O)R^(B), N(R^(A))CO₂R^(B),N(R^(A))SO₂R^(B), N(R^(A))SO₂N(R^(A))R^(B), N(R^(A))C(O)N(R^(A))R^(B),or OC(O)N(R^(A))R^(B), (7) C(O)R^(A), (8) CO₂R^(A), (9)C(O)N(R^(A))R^(B), (10) C(O)—N(R^(A))—C₁₋₆ alkylene-OR^(B) with theproviso that the N(R^(A)) moiety and the OR^(B) moiety are not bothattached to the same carbon of the C₁₋₆ alkylene moiety, (11) SR^(A),(12) S(O)R^(A), (13) SO₂R^(A), (14) SO₂N(R^(A))R^(B), (15)N(R^(A))R^(B), (16) N(R^(A))C(O)R^(B), (17) N(R^(A))C(O)OR^(B); (18)N(R^(A))C(O)N(R^(A))R^(B), (19) N(R^(A))C(O)C(O)N(R^(A))R^(B), (20)N(R^(A))SO₂R^(B), (21) N(R^(A))SO₂N(R^(A))R^(B), (22)OC(O)N(R^(A))R^(B), or (23) Y—R^(K), wherein: Y is a single bond, C₁₋₆alkylene, O, O—C₁₋₆ alkylene, C₁₋₆ alkylene-O, C(O), C(O)—C₁₋₆ alkylene,C₁₋₆ alkylene-C(O), C(O)—C₁₋₆ alkylene-O, C(O)—C₁₋₆ alkylene-O—C₁₋₆alkylene, C(O)N(R^(A)), C(O)N(R^(A))—C₁₋₆ alkylene, C₁₋₆alkylene—C(O)N(R^(A)), C₁₋₆ alkylene—C(O)N(R^(A))—C₁₋₆ alkylene, S(O),S(O)₂, S(O)—C₁₋₆ alkylene, S(O)₂—C₁₋₆ alkylene, C₁₋₆ alkylene-S(O), orC₁₋₆ alkylene-S(O)₂; and R^(K) is CycB, AryB, HetB, or HetQ; or, as analternative, when bond

is a double bond, R² and R³ together with the carbon atoms to which eachis attached form: (i) a benzene ring which is optionally substitutedwith a total of from 1 to 4 substituents wherein (a) from zero to 4substituents are each independently one of substituents (1) to (25) asdefined in part (i) of the definition of AryA and (b) from zero to 2substituents are each independently one of the substituents (1) to (6)as defined in part (ii) of the definition of AryA, or (ii) a 5- or6-membered heteroaromatic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S, wherein the heteroaromatic ringis optionally substituted with a total of from 1 to 3 substituentswherein (a) from zero to 3 substituents are each independently one ofsubstituents (1) to (26) as defined in part (i) of the definition ofHetA and (b) from zero to 2 substituents are each independently one ofthe substituents (1) to (6) as defined in part (ii) of the definition ofHetA; ring A is a 5-membered, saturated or mono-unsaturated heterocyclicring containing in addition to the nitrogen shared with thenaphthyridine ring from 1 to 3 heteroatoms independently selected fromN, O, and S, wherein each S is optionally oxidized to S(O) or S(O)₂; andwherein the saturated or mono-unsaturated heterocyclic ring isoptionally substituted with a total of from 1 to 6 substituents,wherein: (i) from zero to 6 substituents are each independently: (1)halogen, (2) C₁₋₆ alkyl, (3) C₁₋₆ haloalkyl, (4) C₁₋₆ alkyl substitutedwith OH, O—C₁₋₆ alkyl, O—C₁₋₆ haloalkyl, CN, N(R^(A))R^(B),C(O)N(R^(A))R^(B), C(O)R^(A), CO₂R^(A), C(O)—N(R^(A))—C₁₋₆alkylene-OR^(B) with the proviso that the N(R^(A)) moiety and the OR^(B)moiety are not both attached to the same carbon of the C₁₋₆ alkylenemoiety, SR^(A), S(O)R^(A), SO₂R^(A), SO₂N(R^(A))R^(B),N(R^(A))C(O)R^(B), N(R^(A))CO₂R^(B), N(R^(A))SO₂R^(B),N(R^(A))SO₂N(R^(A))R^(B), N(R^(A))C(O)N(R^(A))R^(B), OC(O)N(R^(A))R^(B),or OC(O)R^(A), (5) O—C₁₋₆ alkyl, (6) O—C₁₋₆ haloalkyl, (7) oxo, (8)═C(R^(A))R^(B), (9) C(O)N(R^(A))R^(B), (10) C(O)C(O)N(R^(A))R^(B), (11)C(O)R^(A), (12) CO₂R^(A), (13) SR^(A), (14) S(O)R^(A), (15) SO₂R^(A),(16) SO₂N(R^(A))R^(B), or (17) OH, and (ii) from zero to 2 substituentsare each Z—R^(L), wherein: each Z is independently a single bond, C₁₋₆alkylene, O, O—C₁₋₆ alkylene, C₁₋₆ alkylene-O, C(O), C(O)—C₁₋₆ alkylene,C₁₋₆ alkylene-C(O), C(O)—C₁₋₆ alkylene-O, C(O)—C₁₋₆ alkylene-O—C₁₋₆alkylene, C(O)N(R^(A)), C(O)N(R^(A))—C₁₋₆ alkylene, C₁₋₆alkylene-C(O)N(R^(A)), C₁₋₆ alkylene-C(O)N(R^(A))—C₁₋₆ alkylene, S(O),S(O)₂, S(O)—C₁₋₆ alkylene, S(O)₂—C₁₋₆ alkylene, C₁₋₆ alkylene-S(O), orC₁₋₆ alkylene-S(O)₂; and each R^(L) is independently CycC, AryC, HetC,or HetR; each R^(A) is independently H or C₁₋₆ alkyl; each R^(B) isindependently H or C₁₋₆ alkyl; CycA is a C₃₋₈ cycloalkyl which isoptionally substituted with a total of from 1 to 6 substituents,wherein: (i) from zero to 6 substituents are each independently: (1)halogen, (2) CN (3) C₁₋₆ alkyl, (4) OH, (5) O—C₁₋₆ alkyl, (6) C₁₋₆haloalkyl, or (7) O—C₁₋₆ haloalkyl, and (ii) from zero to 2 substituentsare each independently: (1) CycD, (2) AryD, (3) HetD, (4) HetZ, (5) C₁₋₆alkyl substituted with CycD, AlyD, HetD, or HetZ, or (6) C(O)-HetZ orC(O)C(O)-HetZ; CycB independently has the same definition as CycA; eachCycC independently has the same definition as CycA; AryA is an arylwhich is optionally substituted with a total of from 1 to 5substituents, wherein: (i) from zero to 5 substituents are eachindependently: (1) C₁₋₆ alkyl, (2) C₁₋₆ alkyl substituted with OH,O—C₁₋₆ alkyl, O—C₁₋₆ haloalkyl, CN, NO₂, N(R^(A))R^(B),C(O)N(R^(A))R^(B), C(O)R^(A), CO₂R^(A), SR^(A), S(O)R^(A), SO₂R^(A),SO₂N(R^(A))R^(B), N(R^(A))C(O)R^(B), N(R^(A))CO₂R^(B), N(R^(A))SO₂R^(B),N(R^(A))SO₂N(R^(A))R^(B), OC(O)N(R^(A))R^(B), N(R^(A))C(O)N(R^(A))R^(B),or N(R^(A))C(O)C(O)N(R^(A))R^(B), (3) O—C₁₋₆ alkyl, (4) C₁₋₆ haloalkyl,(5) O—C₁₋₆ haloalkyl, (6) OH, (7) halogen, (8) CN, (9) NO₂, (10)N(R^(A))R^(B), (11) C(O)N(R^(A))R^(B), (12) C(O)R^(A), (13) C(O)—C₁₋₆haloalkyl, (14) C(O)OR^(A), (15) OC(O)N(R^(A))R^(B), (16) SR^(A), (17)S(O)R^(A), (18) SO₂R^(A), (19) SO₂N(R^(A))R^(B), (20) N(R^(A))SO₂R^(B),(21) N(R^(A))SO₂N(R^(A))R^(B), (22) N(R^(A))C(O)R^(B), (23)N(R^(A))C(O)N(R^(A))R^(B), (24) N(R^(A))C(O)C(O)N(R^(A))R^(B), or (25)N(R^(A))CO₂R^(B), and (ii) from zero to 2 substituents are eachindependently: (1) CycD, (2) AryD, (3) HetD, (4) HetZ, (5) C₁₋₆ alkylsubstituted with CycD, AryD, HetD, or HetZ, or (6) C(O)-HetZ orC(O)C(O)-HetZ; AryB independently has the same definition as AryA; eachAryC independently has the same definition as AryA; HetA is a heteroarylwhich is optionally substituted with a total of from 1 to 5substituents, wherein: (i) from zero to 5 substituents are eachindependently: (1) C₁₋₆ alkyl, (2) C₁₋₆ alkyl substituted with OH,O—C₁₋₆ alkyl, O—C₁₋₆ haloalkyl, CN, NO₂, N(R^(A))R^(B),C(O)N(R^(A))R^(B), C(O)R^(A), CO₂R^(A), SR^(A), S(O)R^(A), SO₂R^(A),SO₂N(R^(A))R^(B), N(R^(A))C(O)R^(B), N(R^(A))CO₂R^(B), N(R^(A))SO₂R^(B),N(R^(A))SO₂N(R^(A))R^(B), OC(O)N(R^(A))R^(B), N(R^(A))C(O)N(R^(A))R^(B),or N(R^(A))C(O)C(O)N(R^(A))R^(B), (3) O—C₁₋₆alkyl, (4) C₁₋₆ haloalkyl,(5) O—C₁₋₆ haloalkyl, (6) OH, (7) oxo, (8) halogen, (9) CN, (10) NO₂,(11) N(R^(A))R^(B), (12) C(O)N(R^(A))R^(B), (13) C(O)R^(A), (14)C(O)—C₁₋₆ haloalkyl, (15) C(O)OR^(A), (16) OC(O)N(R^(A))R^(B), (17)SR^(A), (18) S(O)R^(A), (19) SO₂R^(A), (20) SO₂N(R^(A))R^(B), (21)N(R^(A))SO₂R^(B), (22) N(R^(A))SO₂N(R^(A))R^(B), (23) N(R^(A))C(O)R^(B),(24) N(R^(A))C(O)N(R^(A))R^(B), (25) N(R^(A))C(O)C(O)N(R^(A))R^(B), or(26) N(R^(A))CO₂R^(B), and (ii) from zero to 2 substituents are eachindependently: (1) CycD, (2) AryD, (3) HetD, (4) HetZ, (5) C₁₋₆ alkylsubstituted with CycD, AryD, HetD, or HetZ, or (6) C(O)-HetZ orC(O)C(O)-HetZ; HetB independently has the same definition as HetA; eachHetC independently has the same definition as HetA; HetP is (i) a 4- to7-membered, saturated or mono-unsaturated heterocyclic ring containingat least one carbon atom and from 1 to 4 heteroatoms independentlyselected from N, O and S, where each S is optionally oxidized to S(O) orS(O)₂ or (ii) a 6- to 10-membered saturated or mono-unsaturated, bridgedor fused heterobicyclic ring containing from 1 to 4 heteroatomsindependently selected from N, O and S, where each S is optionallyoxidized to S(O) or S(O)₂; and wherein the saturated or mono-unsaturatedheterocyclic or heterobicyclic ring is optionally substituted with atotal of from 1 to 4 substituents, wherein: (i) from zero to 4substituents are each independently halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl,O—C₁₋₆ alkyl, O—C₁₋₆ haloalkyl, oxo, C(O)N(R^(A))R^(B),C(O)C(O)N(R^(A))R^(B), C(O)R^(A), CO₂R^(A), SR^(A), S(O)R^(A), SO₂R^(A),or SO₂N(R^(A))R^(B), and (ii) from zero to 2 substituents are eachindependently CycD, AryD, HetD, or C₁₋₆ alkyl substituted with CycD,AryD, HetD; HetQ independently has the same definition as HetP; eachHetR independently has the same definition as HetP; each CycD isindependently a C₃₋₈ cycloalkyl which is optionally substituted withfrom 1 to 4 substituents each of which is independently halogen, C₁₋₆alkyl, OH, O—C₁₋₆ alkyl, or C₁₋₆ haloalkyl; each AryD is independentlyphenyl or naphthyl, wherein the phenyl or naphthyl is optionallysubstituted with from 1 to 5 substituents each of which is independentlyany one of the substituents (1) to (25) as set forth above in part (i)of the definition of AryA; each HetD is independently a 5- or 6-memberedheteroaromatic ring containing from 1 to 4 heteroatoms independentlyselected from N, O and S, wherein the heteroaromatic ring is optionallysubstituted with from 1 to 4 substituents each of which is independentlyany one of the substituents (1) to (26) as set forth above in part (i)of the definition of HetA; each HetZ is independently a 4- to7-membered, saturated or mono-unsaturated heterocyclic ring containingat least one carbon atom and from 1 to 4 heteroatoms independentlyselected from N, O and S, where each S is optionally oxidized to S(O) orS(O)₂, wherein the saturated or mono-unsaturated heterocyclic ring isoptionally substituted with from 1 to 4 substituents each of which isindependently halogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, O—C₁₋₆alkyl, O—C₁₋₆haloalkyl, oxo, C(O)N(R^(A))R^(B), C(O)C(O)N(R^(A))R^(B), C(O)R^(A),CO₂R^(A), SR^(A), S(O)R^(A), SO₂R^(A), or SO₂N(R^(A))R^(B); each aryl isindependently (i) phenyl, (ii) a 9- or 10-membered bicyclic, fusedcarbocyclic ring system in which at least one ring is aromatic, or (iii)an 11- to 14-membered tricyclic, fused carbocyclic ring system in whichat least one ring is aromatic; and each heteroaryl is independently (i)a 5- or 6-membered heteroaromatic ring containing from 1 to 4heteroatoms independently selected from N, O and S, wherein each N isoptionally in the form of an oxide, or (ii) a 9- or 10-memberedbicyclic, fused ring system containing from 1 to 4 heteroatomsindependently selected from N, O and S, wherein either one or both ofthe rings contain one or more of the heteroatoms, at least one ring isaromatic, each N is optionally in the form of an oxide, and each S in aring which is not aromatic is optionally S(O) or S(O)₂.
 2. A compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹ is C₁₋₆ alkyl substituted with R^(J).
 3. A compound accordingto claim 2, or a pharmaceutically acceptable salt thereof, wherein R^(J)is AryA or HetA.
 4. A compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein: R² is H or C₁₋₆alkyl; and R³ is H, C₁₋₆ alkyl, C(O)N(R^(A))R^(B), SO₂N(R^(A))R^(B), orC₁₋₆ alkyl substituted with C(O)N(R^(A))R^(B) or SO₂N(R^(A))R^(B).
 5. Acompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein the compound is a compound of Formula IIb:

wherein W is O or N—R⁸; R⁶ and R⁷ are each independently H, C₁₋₆ alkyl,or C₁₋₆ alkyl substituted with OH; and R⁸ is: (1) H, (2) C₁₋₆ alkyl, (3)C₁₋₆ haloalkyl, (4) C₁₋₆ alkyl substituted with OH, O—C₁₋₆ alkyl,N(R^(A))R^(B), C(O)N(R^(A))R^(B), C(O)R^(A), CO₂R^(A),C(O)—N(R^(A))—C₁₋₆ alkylene-OR^(B) with the proviso that the N(R^(A))moiety and the OR^(B) moiety are not both attached to the same carbon ofthe C₁₋₆ alkylene moiety, S(O)R^(A), SO₂R^(A), SO₂N(R^(A))R^(B),N(R^(A))C(O)R^(B), N(R^(A))SO₂R^(B), or OC(O)R^(A), or (5) Z—R^(L).
 6. Acompound according to claim 5, or a pharmaceutically acceptable saltthereof, wherein R¹ is:

the asterisk * denotes the point of attachment of R¹ to the rest of thecompound; V¹ and V² are each independently: (1) H, (2) C₁₋₄ alkyl, (3)OH, (4) O—C₁₋₄ alkyl, (5) C₁₋₄ haloalkyl, (6) O—C₁₋₄ haloalkyl, (7)halogen, (8) CN, (9) N(R^(A))R^(B), (10) C(O)N(R^(A))R^(B), (11)C(O)R^(A), (12) C(O)OR^(A), (13) SR^(A), (14) S(O)R^(A), (15) SO₂R^(A),(16) N(R^(A))SO₂R^(B), (17) N(R^(A))SO₂N(R^(A))R^(B), (18)N(R^(A))C(O)R^(B), (19) N(R^(A))C(O)C(O)N(R^(A))R^(B), (20) HetD, (21)HetZ, or (22) C(O)-HetZ, wherein HetD is a 5- or 6-memberedheteroaromatic ring containing a total of from 1 to 3 heteroatomsindependently selected from 1 to 3 N atoms, from zero to 1 O atom, andfrom zero to 1 S atom, wherein the heteroaromatic ring is optionallysubstituted with 1 or 2 substituents each of which is independently C₁₋₄alkyl, OH, O—C₁₋₄ alkyl, halogen, CN, C(O)N(R^(A))R^(B), C(O)R^(A),C(O)OR^(A), or SO₂R^(A), HetZ is a 5- or 6-membered saturatedheterocyclic ring containing a total of from 1 to 2 heteroatoms selectedfrom 1 to 2 N atoms, zero to 1 O atom, and zero to 1 S atom, wherein theS atom is optionally S(O) or SO₂, wherein the saturated heterocyclicring is optionally substituted with from 1 to 2 substituents each ofwhich is independently C₁₋₄ alkyl, oxo, C(O)N(R^(A))R^(B), C(O)R^(A),CO₂R^(A), or SO₂R^(A), and with the proviso that when HetZ is attachedto the rest of the compound via the C(O) moiety, then HetZ is attachedto the C(O) via a ring N atom; or alternatively V¹ and V² arerespectively located on adjacent carbons in the phenyl ring and togetherform methylenedioxy or ethylenedioxy; and V³ is: (1) H, (2) C₁₋₄ alkyl,(3) O—C₁₋₄ alkyl, (4) C₁₋₄ haloalkyl, (5) O—C₁₋₄ haloalkyl, or (6)halogen.
 7. A compound according to claim 6, or a pharmaceuticallyacceptable salt thereof, wherein the compound is of Formula IIId:

wherein: R² and R³ are each independently H or C₁₋₄ alkyl; one of R⁶ andR⁷ is H, C₁₋₄ alkyl, or C₁₋₄ alkyl substituted with OH, and the other ofR⁶ and R⁷ is H or C₁₋₄ alkyl; R⁸ is: (1) H, (2) C₁₋₄ alkyl, (3) C₁₋₄haloalkyl, (4) C₁₋₄ alkyl substituted with OH, O—C₁₋₄ alkyl,N(R^(A))R^(B), C(O)N(R^(A))R^(B), C(O)R^(A), CO₂R^(A), S(O)R^(A),SO₂R^(A), SO₂N(R^(A))R^(B), N(R^(A))C(O)R^(B), N(R^(A))SO₂R^(B), orOC(O)R^(A), (5) C₁₋₄ alkylene-HetC, or (6) C₁₋₄ alkylene-HetR; HetC is a5- or 6-membered heteroaromatic ring containing a total of from 1 to 3heteroatoms independently selected from 1 to 3 N atoms, from zero to 1 Oatom, and from zero to 1 S atom, wherein the heteroaromatic ring isoptionally substituted with 1 or 2 substituents each of which isindependently C₁₋₄ alkyl, OH, O—C₁₋₄ alkyl, halogen, CN,C(O)N(R^(A))R^(B), C(O)R^(A), C(O)OR^(A), or SO₂R^(A); HetR is a 5- or6-membered saturated heterocyclic ring containing a total of from 1 to 2heteroatoms selected from 1 to 2 N atoms, zero to 1 O atom, and zero to1 S atom, wherein the S atom is optionally S(O) or SO₂, wherein thesaturated heterocyclic ring is optionally substituted with from 1 to 2substituents each of which is independently C₁₋₄ alkyl, oxo,C(O)N(R^(A))R^(B), C(O)R^(A), CO₂R^(A), or SO₂R^(A); each R^(A)isindependently H or C₁₋₄ alkyl; and each R⁸ is independently H or C₁₋₄alkyl.
 8. A compound according to claim 7, or a pharmaceuticallyacceptable salt thereof, wherein: bond

in the ring is a single bond; R² and R³ are each independently H or CH₃;one of R⁶ and R⁷ is H, CH₃, CH₂CH₃, CH₂CH₂CH3, CH(CH₃)₂ or (CH₂)₁₋₃—OH,and the other of R⁶ and R⁷ is H or CH³; R⁸ is: (1) H, (2) CH₃, (3)CH₂CH₃, (4) CH₂CH₂CH₃, (5) CH(CH₃)₂, (6) CH₂CH₂CH₂CH₃, (7) C(CH₃)₃, (8)CH₂CH(CH₃)₂, (9) CH(CH₃)CH₂CH₃, (10) CF₃, (11) CH₂CF₃, (12) (CH₂)₂₋₄—U,wherein U is OH, OCH₃, N(R^(A))R^(B), N(R^(A))C(O)R^(B),N(R^(A))SO₂R^(B), or OC(O)R^(A), (13) (CH₂)₁₋₄—V, wherein V isC(O)N(R^(A))R^(B), C(O)R^(A), CO₂R^(A), S(O)R^(A), SO₂R^(A), orSO₂N(R^(A))R^(B), (14) (CH₂)₂₋₄-HetC, or (15) (CH₂)₂₋₄-HetR; HetC is a5-membered heteroaromatic ring selected from the group consisting of:

HetR is a 5- or 6-membered saturated heterocyclic ring selected from thegroup consisting of:

the asterisk * in HetC and HetR denotes the point of attachment to therest of the molecule; each R^(A) is independently H or CH₃; each R^(B)is independently H or CH₃; V¹ and V² are each independently: (1) H, (2)CH₃, (3) CF₃, (4) OH, (5) OCH₃, (6) Cl, Br, or F, (7) CN, (8) C(O)NH₂,(9) C(O)NH(CH₃), (10) C(O)N(CH₃)₂, or (11) SO₂CH₃; and V³ is H, Cl, Br,F, CH₃, or OCH₃.
 9. The compound according to claim 1, or apharmaceutically acceptable salt thereof, which is a compound selectedfrom the group consisting of:8-(3-chloro-4-fluorobenzyl)-6-hydroxy-1,3-dimethyl-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine-2,5,7(3H)-trione;and8-(3-chloro-4-fluorobenzyl)-6-hydroxy-1,3,3-trimethyl-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine-2,5,7(3H)-trione.10. The compound according to claim 1, or a pharmaceutically acceptablesalt thereof, which is a compound selected from the group consisting of:2-[8-(3-chloro-4-fluorobenzyl)-6-hydroxy-3,3-dimethyl-2,5,7-trioxo-2,3,7,8,9,10-hexahydroimidazo[2,1-a]-2,6-naphthyridin-1(5H)-yl]-N,N-dimethylacetamide;2-[8-(3-chloro-4-fluorobenzyl)-6-hydroxy-3,3-dimethyl-2,5,7-trioxo-2,3,7,8,9,10-hexahydroimidazo[2,1-a]-2,6-naphthyridin-1(5H)-yl]-N-methylacetamide;2-[8-(3-chloro-4-fluorobenzyl)-6-hydroxy-3,3-dimethyl-2,5,7-trioxo-2,3,7,8,9,10-hexahydroimidazo[2,1-a]-2,6-naphthyridin-1(5H)-yl]acetamide;8-(3-chloro-4-fluorobenzyl)-6-hydroxy-1-(2-hydroxyethyl)-3,3-dimethyl-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine-2,5,7(3H)-trione;8-(3-chloro-4-fluorobenzyl)-6-hydroxy-1-(3-hydroxypropyl)-3,3-dimethyl-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine-2,5,7(3H)-trione;8-(3-chloro-4-fluorobenzyl)-6-hydroxy-1-(4-hydroxybutyl)-3,3-dimethyl-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine-2,5,7(3H)-trione;8-(3-chloro-4-fluorobenzyl)-6-hydroxy-1-(2-acetyloxyethyl)-3,3-dimethyl-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine-2,5,7(3H)-trione;8-(3-chloro-4-fluorobenzyl)-6-hydroxy-1-(3-acetyloxypropyl)-3,3-dimethyl-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine-2,5,7(3H)-trione;8-(3-chloro-4-fluorobenzyl)-6-hydroxy-1-(4-acetyloxybutyl)-3,3-dimethyl-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine-2,5,7(3H)-trione;8-(3-chloro-4-fluorobenzyl)-6-hydroxy-1,3-bis(2-hydroxyethyl)-3-methyl-1,8,9,10-tetrahydroimidazo[2,1-a]-2,6-naphthyridine-2,5,7(3H)-trione.11. A pharmaceutical composition comprising an effective amount of acompound according to claim 1, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.
 12. A method for thetreatment of infection by HIV or for the treatment of AIDS in a subjectin need thereof, which comprises administering to the subject aneffective amount of the compound according to claim 1, or apharmaceutically acceptable salt thereof.